JP2796944B2 - Serine derivatives having anti-CCK activity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a serine derivative compound and a compound having potent and selective antagonistic activity against cholecystokinin (CCK) receptor.

[0002]

2. Description of the Related Art CCK is a peptide gastrointestinal hormone released into the blood from the mucosal epithelium of the duodenum by degradation products of proteins and fats in food. It is known to exert physiological effects such as a stimulating effect. Subsequently, it was revealed that CCK also exists in the central nervous system such as the brain, and CCK has become known as a cerebral intestinal peptide hormone having both a function as a neurotransmitter and a function as a gastrointestinal hormone. As its effects, there are currently reported effects such as promotion of pancreatic exocrine secretion, promotion of gallbladder contraction, promotion of intestinal peristalsis, suppression of small intestinal absorption, and increase in gastric acid secretion. CCK is CCK58, CCK39,
Peptides such as CCK33 and CCK8 have been isolated from tissues, and their structures are common at the four C-terminal amino acid residues of the gastrointestinal hormone gastrin. recent years,
As a result of research on CCK and CCK receptor, CCK-A receptor as a peripheral receptor and CCK as a central receptor
-B receptor has been found to be present,
Various physiologically active effects have also been reported for antagonists against these. For example, CCK-A receptor antagonists are known to inhibit pancreatic exocrine secretion, inhibit gallbladder contraction, promote gastric emptying, inhibit intestinal motility, and CCK-B receptor antagonists are known to have antiulcer activity. I have. Therefore, it has been speculated that CCK receptor antagonists may be useful for treating diseases such as pancreatitis, pancreatic cancer, peptic ulcer, bile dysfunction, colitis and the like (Japanese Patent Application Laid-Open No. 62-18124).
6, JP-A-63-201156, JP-A-2-11177
4 etc.). In particular, since it has an important effect on the pancreas, such as stimulation of pancreatic enzyme secretion, it is highly likely that CCK is mediated through binding to a receptor as one of the factors for the development and progression of acute pancreatitis. Receptor antagonists are expected to be useful in treating pancreatitis. Against this background,
Many compounds that specifically and competitively inhibit the CCK receptor have been reported, and their clinical application has attracted attention. For example, a glutamate derivative CR-1505 (Roxiglumide, JP-A-62-181246) and a benzodiazepine derivative FK-480 (JP-A-2-111774), which are CCK-A receptor antagonists, are promising therapeutic agents for pancreatitis. ing.

[0003]

An object of the present invention is to provide a serine derivative having a strong inhibitory activity on CCK and a selective competitive inhibitory effect on CCK-A receptor. That is, the present invention is a CCK receptor antagonist which is useful for the prevention and treatment of pancreatitis, pancreatic cancer, duodenal ulcer, gastric ulcer, peptic ulcer, colitis, dysfunction of schizophrenia, etc. It is an object to provide an effective serine derivative.

[0004]

The compound of the present invention that achieves the above object relates to a compound represented by the following general formula (I).

Embedded image

[0005] wherein, (1) A represents CH or nitrogen atom, to form a piperidine ring or piperazine ring of 6-membered ring bonded to together with N in the formula, 1-position of the N in the ring Against
4 position to occupy, (2) _{R 1} is (i) straight or branched chain alkyl group having 1 to 4 carbon atoms, (ii) a cyclohexyl group, (i
ii) dibenzo [a, d in which unsubstituted or substituted phenyl group substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms, (iv) pyridyl group and (v) two R _1's are bonded together with> CH- group A group selected from the group consisting of a cycloheptenyl group and a fluorenyl group, and (3) R ₂ represents (i)
(4) a group selected from the group consisting of a phenyl group, a pyridyl group, a pyrazyl group, and (ii) a phosphonopyridyl group substituted with a carboxyl group or a substituted carboxyl group;
R ₃ represents an indolyl group which is unsubstituted or substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms and a methoxycarbonylethyl group. ]

The compound of the general formula (I) is a serine derivative of the following formula (II):

Embedded image Therefore, the basic skeleton of the compound of the general formula (I) is represented by the general formula (III)

Embedded image It is represented by Since the compound of the present invention has an asymmetric carbon atom at the 2-position in the basic skeleton, it is obtained as a racemate or an enantiomer.

[0007] When A in the general formula (I) is CH indicates the bond to piperidine ring and N in the formula, also
When it is a nitrogen atom, it represents a piperazine ring, and when R ₁ is a phenyl group,

Embedded image Is configured. These groups are particularly desirable for the purposes of the present invention. R ₁ is preferably a butyl group or an isopropyl group as a linear or branched alkyl group having 1 to 4 carbon atoms in addition to the phenyl group, and a cyclohexyl group is selected as a cyclic aliphatic hydrocarbon group. Examples of the substituted phenyl group include a phenyl group substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms, and a phenyl group substituted with a fluorine atom or a methoxy group is preferable. Pyridyl group is an example of a heterocyclic group, further two R ₁ is> CH
The tricyclic carbocyclic group bonded with the group includes a dibenzo [a, d] cycloheptenyl group or a fluorenyl group. Examples of the starting compounds having these groups are shown in Production Examples described later. R ₂ is a substituent of an —OH group of serine together with a thio group (—S—), and R ₃ is an indolyl group, particularly preferably an indol-2-yl group as an organic group of an acyl group in an —NH ₂ group of serine. Is specified, and
Examples of the substituent include a halogen atom, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms and a methoxycarbonylethyl group. A chlorine atom is preferable as the halogen atom, and a methoxy group is preferable as the alkoxy group. Salts of the compounds of general formula (I) means that the substituent group R ₂ is meant salts for a carboxyl group, also produces an acid addition salt derived from the basic group of the compound. Specific examples of the compound of the general formula (I) are shown in Table 1 below. The compound numbers in the table are the same as the example numbers described below. And R ₁ of compound 18 and 19 in Table 1 shows the two R ₁ is> CH- tricyclic carbocyclic group bonded with groups.

[0008]

[Table 1]

The steps of the method for producing the compound of the present invention are shown below. 1st process Following formula (IV)

Embedded image (Wherein Boc represents a t-butoxycarbonyl group and R ₁₁ represents a tetrahydropyranyl group). A compound represented by the following formula (V)

Embedded image (Wherein A and R ₁ are the same as A and R ₁ in the compound of the formula (I)).

Embedded image (Wherein R ₁₁ represents a tetrahydropyranyl group).

Second step The compound of the formula (VI) is hydrolyzed to give the following formula (VII)

Embedded image To obtain the compound represented by

Third step: The compound of formula (VII) is added to methanesulfonyl chloride or p-
By reacting toluenesulfonyl chloride, the following formula (VIII)

Embedded image (Wherein R ₁₂ represents a mesyl group or a tosyl group).

Fourth Step A compound of the formula (VIII) and a compound of the following formula (IX)

Embedded image HS-R ₂ (IX) (wherein R ₂ is Formula (the same as R ₂ of the compound of I)) is reacted with a compound represented by the following formula (X)

Embedded image (Wherein R ₂ is the same as R ₂ in formula (IX)).

Fifth Step The protecting group Boc of the compound of the formula (X) is eliminated to give the following formula (XI)

Embedded image To obtain the compound represented by

Sixth Step The compound of the formula (XI) is converted to the compound of the following formula (XII)

Embedded image R ₃ COOH (XII) (wherein, R ₃ is the same as group R ₃ of the compound of formula (I).) A compound represented by or reacted with a reactive derivative thereof formula (I ) Is obtained.

Next, the reaction conditions of each step will be described.
As a starting material compound, Nt-butoxycarbonyl-O-tetrahydropyranyl-L represented by the formula (IV) in which the amino group of serine is protected by a t-butoxycarbonyl group and the -OH group is protected by a tetrahydropyranyl group. -Use serine.

Step 1 Compound (VI) is obtained by condensing compound (IV) with compound (V). As the condensing reagent to be used, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, or the like is used. 1-hydroxybenztriazole (HOBT) is appropriately used as an auxiliary agent. Examples of the solvent used include tetrahydrofuran, ethyl acetate, acetonitrile, dimethoxyethane, dimethylformamide, dichloromethane and the like. The reaction temperature is preferably −10 to 30 ° C., and the reaction time is preferably 30 minutes to 20 hours, but is not limited thereto.

Step 2 The compound (VI) is hydrolyzed under acidic conditions to remove the protecting group of the -OH group to give the compound (VII) (alcohol). As the hydrolysis conditions, for example, a 1N hydrochloric acid aqueous solution in tetrahydrofuran is added and stirred to easily obtain the desired product.

Third Step Compound (VII) is converted to the corresponding compound (VIII) (sulfonate) by reacting with a sulfonyl halide such as methanesulfonyl chloride or paratoluenesulfonyl chloride in the presence of a base. As a solvent used in this reaction, dichloromethane, chloroform, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide and the like and a mixture thereof are used. As the base to be used, a tertiary amine such as triethylamine, pyridine, diisopropylethylamine, N, N-diethylaniline or an inorganic base such as potassium carbonate can be used. Reaction temperature is -20 to 50 ° C,
Desirably, it is around −10 ° C.

Fourth Step The compound (VIII) (sulfonate compound) is reacted with a compound (IX) of the formula HS-R ₂ which is a nucleophile to obtain a compound (X) which has undergone a substitution reaction. As the compound (IX), thiol compounds (preferably used as salts) such as 2-mercaptobenzoic acid, methyl 2-mercaptonicotinate, and 2-methoxycarbonyl-3-mercaptopyrazine are used. As the reaction solvent, dimethylformamide, dimethylsulfoxide, N, N'-dimethylimidazolidinone, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile and the like may be used, and if necessary, a base such as potassium carbonate and triethylamine may be used.

Step 5 Boc group (t-butoxycarbonyl group) of compound (X)
Can be easily removed by acid treatment with trifluoroacetic acid or hydrogen chloride / ethyl acetate to obtain the corresponding amino compound (XI).

Sixth Step Compound (I), which is an amide corresponding to compound (XI), which is obtained by condensing compound (XI) with compound (XII), ie, unsubstituted or substituted indole-2-carboxylic acid or a reactive acid derivative thereof, ie, the present invention Is obtained. The reaction conditions are the same as in the first step.

Accompanying Step The carboxyl group in the group of R ₂ can be converted to a salt or ester group thereof, and if the compound itself is basic, it can be converted to an acid addition salt thereof. As shown in FIG. 5, acrylic acid may be bonded by addition.

[0023]

The following are examples of the compounds of the present invention. The production examples of the raw material compounds used in the examples will be omitted by showing production examples of the raw material compounds used in the examples, but the present invention is not limited thereto.

Production Examples of Starting Compounds Production Example 1 1-bis (4-methoxyphenyl) methylpiperazine (compound of formula V) (1) bis (4-methoxyphenyl) methanol 4,4'-dimethoxybenzophenone 4.84 g Sodium borohydride 1.03 in 80 ml ethanol solution
g was added and stirred at room temperature for 7 hours. Then add water and add 30
After stirring for minutes, the mixture was concentrated to about 20 ml. Further, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate (50 ml × 3), washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.84 g of the title compound. Yield: 99% NMR (CDCl ₃ ) δ: 2.30 (1H, bs), 3.76 (6H, s),
5.74 (1H, bs), 6.85 (4H, d, J = 6.6Hz), 7.26 (4H, d, J = 6.6H
z)

(2) 1-formyl-4-bis (4-methoxyphenyl) methylpiperazine 1.22 g of the above compound (1), triethylamine 1.0
1 g was dissolved in 15 ml of dichloromethane, and a solution of 630 mg of methanesulfonyl chloride in 5 ml of dichloromethane was added dropwise at -15 ° C over 10 minutes. After stirring at the same temperature for 30 minutes, a solution of 1.14 g of N-formylpiperazine in 5 ml of dichloromethane was added dropwise over 10 minutes.
Stirred at C for 1 hour. The reaction solution is made alkaline by adding a saturated sodium hydrogen carbonate solution, and dichloromethane (10
ml × 3). Next, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.80 g of a residue. This was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 1.68 g of the title compound. Yield: 98% NMR (CDCl ₃ ) δ: 2.3 to 2.4 (4H, m), 3.34 (2H, b
t), 3.52 (2H, bt), 3.75 (6H, s), 4.19 (1H, s), 6.82 (4H,
d, J = 6.6Hz), 7.29 (4H, d, J = 6.6Hz), 7.98 (1H, s)

(3) 1-bis (4-methoxyphenyl)
Methyl piperazine To 1.68 g of the above compound (2), 6 m of tetrahydrofuran was added.
1, 9 ml of methanol and 9 ml of a 10% aqueous sodium hydroxide solution were added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was concentrated to about 10 ml, saturated with sodium chloride, and extracted with dichloromethane (20 ml × 4). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.48 g of the title compound. Yield: 95% NMR (CDCl ₃ ) δ: 1.48 (1H, bs), 2.32 (4H, bt),
2.86 (4H, t, J = 4.9Hz), 3.75 (6H, s), 4.12 (1H, s), 6.80 (4
(H, d, J = 6.6Hz), 7.31 (4H, d, J = 6.6Hz)

The following compounds were prepared in a similar manner. 1.1-isopropylpiperazine NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.6 Hz), 1.62 (1
H, bs), 2.52 (4H, bt), 2.62 (1H, sep, J = 6.6Hz), 2.90 (4H, b
t) 2.1- bis (2-pyridyl) methyl-piperazine _{NMR (CDCl 3) δ: 2.3~2.5} (4H, m), 2.52 (1H, b
s), 2.8-3.0 (4H, m), 4.65 (1H, s), 7.0-7.2 (2H, m),
7.5~7.7 (4H, m), 8.4~8.6 (2H, m) 3.1- (1- butylpentyl) piperazine _{NMR (CDCl 3) δ: 0.8~1.0} (6H, m), 1.2~1.6
(12H, m), 1.65 (1H, bs), 2.2 to 2.3 (1H, m), 2.4 to 2.6 (4H,
m), 2.8~3.0 (4H, m ) 4.1- bis (4-fluorophenyl) methylpiperazine _{NMR (CDCl 3) δ: 0.63} (1H, s), 2.1~2.5 (4H,
m), 2.7 to 3.0 (4H, m), 4.20 (1H, s), 6.8 to 7.1 (4H, m), 7.
2~7.4 (4H, m) 5.1- diisopropyl methylpiperazine _{NMR (CDCl 3) δ: 0.8~1.0} (12H, m), 1.60 (1H,
bs), 1.8~2.0 (3H, m ), 2.4~2.6 (4H, m), 2.7~2.9 (4H, m) 6.1- dicyclohexyl methylpiperazine _{NMR (CDCl 3) δ: 0.9~1.4} (11H, m ), 1.5-1.
8 (12H, m), 1.8 ~ 2.0 (1H, m), 2.6 ~ 2.8 (4H, m), 2.8 ~
3.0 (4H, m) 7.1- ( 9- fluorenyl) piperazine _{NMR (CDCl 3) δ: 1.46} (1H, bs), 2.62 (4H, dd, J =
5.0Hz, 4.3Hz), 2.84 (4H, dd, J = 5.0Hz, 4.3Hz), 4.80 (1H,
s), 7.2 ~7.4 (4H, m), 7.6~7.7 (4H, m) 8.1- (10,11- dihydro -5H- dibenzo [a, d] cycloheptene-5-yl) piperazine NMR (CDCl ₃ ) Δ: 1.70 (1H, bs), 2.1 ~ 2.3 (4H,
m), 2.7 to 2.9 (6H, m), 3.94 (1H, s), 3.9 to 4.1 (2H, m), 7.
9-8.2 (8H, m)

Production Example 2 Ethyl 2-mercaptonicotinate (compound of formula IX) (1) Ethyl 2-chloronicotinate 25.7 g of 2-chloronicotinic acid was dissolved in 350 ml of dimethylformamide, 23.6 g of potassium carbonate and iodine were added. 15.8 ml of ethyl chloride was added and the mixture was stirred at room temperature for 18 hours.
Water was added to the reaction solution, extracted with ethyl acetate (200 ml × 3), washed with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 29.7 g of the title compound.
Yield: 98% NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 4.41 (2
H, q, J = 7.1Hz), 7.35 (1H, dd, J = 7.5Hz, 5.9Hz), 8.16 (1H, d
d, J = 7.5Hz, 1.7Hz), 8.52 (1H, dd, J = 5.9Hz, 1.7Hz)

(2) Ethyl 2-mercaptonicotinate Sodium sulfide nonahydrate 55.9 g, sulfur powder 59.7
250 ml of ethanol was added to g, and the mixture was heated under reflux for 1.5 hours. 28.8 g of ethyl 2-chloronicotinate was added to this solution.
Of ethanol was added and stirred at 70 ° C. for 4 hours. After cooling to room temperature, the reaction solution was added to 240 ml of a 2N aqueous hydrochloric acid solution cooled with ice. With sodium bicarbonate
The mixture was adjusted to H6, and insolubles were removed by filtration. About 250 ml of filtrate
After concentration with sodium chloride, the mixture was extracted with dichloromethane / ethanol = 9/1 (100 ml × 3). After washing with a saturated saline solution, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 22.4 g of the title compound. Yield: 79% NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 4.42 (2
H, q, J = 7.1Hz), 6.89 (1H, dd, J = 7.5Hz, 5.9Hz), 7.89 (1H, d
d, J = 5.9Hz, 1.7Hz), 7.96 (1H, dd, J = 7.5Hz, 1.7Hz)

Production Example 3 Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine (compound of formula IV) 7.65 g of Nt-butoxycarbonyl-L-serine,
3.88 g of 3,4-dihydro-2H-pyran was dissolved in 60 ml of dichloromethane, and 0.47 g of pyridinium p-toluenesulfonate was added, followed by stirring at room temperature for 3 hours.
The reaction solution was washed with water and saturated saline, and the solvent was distilled off under reduced pressure to obtain 9.90 g of the title compound. Yield: 92%

Example 1 (1) (S) -4-diphenylmethyl-1- (3-hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Nt-butoxycarbonyl-O-tetrahydropyranyl-L- Dissolve 2.89 g of serine, 2.52 g of 1-benzhydrylpiperazine and 1.53 g of 1-hydroxybenzotriazole monohydrate in 30 ml of dichloromethane,
To this, 1.92 g of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride was added and 14
Stirred for hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.98 g of a residue. 20 ml of tetrahydrofuran and 30 ml of 1N hydrochloric acid were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and ethyl acetate (50 ml) was added.
× 3), and then washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 4.56 g of a residue.
Obtained. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to obtain 2.31 g of the title compound (1). Yield: 53%

NMR (CDCl ₃ ) δ: 1.42 (9H, s),
2.3 to 2.5 (4H, m), 3.4 to 3.8 (7H, m), 4.24 (1H, s), 4.5 to
4.7 (1H, m), 5.72 (1H, bd), 7.1 ~ 7.3 (6H, m), 7.3 ~ 7.5
(4H, m)

(2) (S) -4-diphenylmethyl-1
-(3-mesyloxy-2-t-butoxycarbonylamino) propionylpiperazine 2.20 g of the above compound (1), triethylamine 1.1
15 g of dichloromethane was added to 1 g and dissolved, and methanesulfonyl chloride 1.15 g of dichloromethane 5 ml
The solution was added dropwise at −10 ° C. over 30 minutes, and then stirred for 30 minutes. Dichloromethane was added to the reaction solution, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.53 g of the title compound (2). Yield: 98%

NMR (CDCl ₃ ) δ: 1.42 (9H, s),
2.3 ~ 2.5 (4H, m), 3.00 (3H, s), 3.5 ~ 3.7 (4H, m), 4.24 (1
H, s), 4.2 ~ 4.4 (2H, m), 4.8 ~ 5.0 (1H, m), 5.54 (1H, bd),
7.1 to 7.3 (6H, m), 7.3 to 7.5 (4H, m)

(3) (R) -4-diphenylmethyl-1
-[3- (3-Methoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperazine 2.53 g of the above compound (2), 1.24 g of methyl 2-mercaptonicotinate, potassium carbonate 1. 50 ml of dimethylformamide was added to 01 g, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and ethyl acetate (70 ml 3
), Washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was 2.89.
g was obtained. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to obtain 2.60 g of the title compound (3). Yield: 90%

NMR (CDCl ₃ ) δ: 1.36 (9H, s),
2.2 to 2.6 (4H, m), 3.0 to 3.2 (1H, m), 3.5 to 3.9 (5H, m), 3.
90 (3H, s), 4.23 (1H, s), 4.9-5.1 (1H, m), 5.47 (1H, bd),
7.04 (1H, dd, J = 7.8Hz, 4.9Hz), 7.1 ~ 7.3 (6H, m), 7.4 ~ 7.
5 (4H, m), 8.16 (1H, dd, J = 7.8Hz, 1.8Hz), 8.40 (1H, dd, J =
(4.9Hz, 1.8Hz)

(4) (R) -1- [2-amino-3-
(3-methoxycarbonylpyridin-2-yl) thio]
Propionyl-4-diphenylmethylpiperazine To 2.36 g of the above compound (3), 15 ml of 4N hydrogen chloride (ethyl acetate solution) was added, and the mixture was stirred at room temperature for 1.5 hours.
The reaction solution was alkalified by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate (50 ml × 3), washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.92 g of the title compound (4).
Yield: 98%

NMR (CDCl ₃ ) δ: 1.92 (2H, bs),
2.2 ~ 2.6 (4H, m), 2.84 (1H, dd, J = 13.9Hz, 9.5Hz), 3.5 ~
3.9 (5H, m), 3.93 (3H, s), 4.0 ~ 4.1 (1H, m), 4.24 (1H, s),
7.04 (1H, dd, J = 7.8Hz, 4.9Hz), 7.1 ~ 7.3 (6H, m), 7.4 ~ 7.
5 (4H, m), 8.19 (1H, dd, J = 7.8Hz, 1.8Hz), 8.34 (1H, dd, J =
(4.9Hz, 1.8Hz)

(5) (R) -4-diphenylmethyl-1
-[2- (indol-2-yl) carbonylamino-
3- (3-Methoxycarbonylpyridin-2-yl) thio] propionylpiperazine To 735 mg of the above compound (4), 266 mg of indole-2-carboxylic acid, and 252 mg of 1-hydroxybenzotriazole monohydrate, 15 ml of dichloromethane was added. 1-ethyl-3- (3-dimethylaminopropyl)
316 mg of carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give the title compound (5) 836.
mg was obtained. Yield: 88%

IR (KBr) cm ^-1 : 1720, 1630, 155
0, 1400 NMR (CDCl ₃ ) δ: 2.38 (4H, bs), 3.49 (1H, dd, J =
13.9Hz, 9.5Hz), 3.5 to 3.9 (5H, m), 3.81 (3H, s), 4.19 (1
H, s), 5.5 ~ 5.7 (1H, m), 6.9 ~ 7.4 (15H, m), 7.54 (1H, d,
J = 7.6Hz), 7.92 (1H, d, J = 7.6Hz), 8.13 (1H, dd, J = 7.6Hz,
1.8Hz), 8.42 (1H, dd, J = 5.6Hz, 1.8Hz), 9.96 (1H, s) Specific rotation: [α] _D ²⁵ = -70.0 ° (c = 0.9, D
MSO)

(6) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4-diphenylmethylpiperazine 697 mg of the above compound (5) was added in 8 ml of tetrahydrofuran
139 mg of lithium hydroxide monohydrate, water 8
Then, 4 ml of methanol and 4 ml of methanol were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to about 10 ml, neutralized with a 10% aqueous citric acid solution, and diluted with dichloromethane (30 ml ×
Extracted in 3). After washing with saturated saline, drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound (6) 6
13 mg were obtained. Yield: 90%

IR (KBr) cm ^-1 : 1700, 1630, 155
0, 1390 NMR (CDCl ₃ ) δ: 2.47 (2H, bs), 2.59 (2H, bs),
2.88 (1H, bt), 3.5 ~ 4.0 (4H, m), 4.1 ~ 4.3 (1H, m), 4.29
(1H, s), 5.5 to 5.7 (1H, m), 6.9 to 7.6 (16H, m), 7.68 (1H,
d, J = 8.9Hz), 8.10 (1H, dd, J = 7.7Hz, 1.8Hz), 8.42 (1H, dd, J
= 4.9Hz, 1.8Hz), 11.00 (1H, s) Specific rotation: [α] _D ²⁵ = -66.9 ° (c = 1.2, D
MSO)

(7) Hydrochloride of the above compound (6) 1.24 g of the above compound (6) was added to 20 ml of dichloromethane.
And dissolved in 4N hydrogen chloride (ethyl acetate solution) 0.5ml
Was added and stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure to obtain 1.31 g of the hydrochloride of the title compound (6). Melting point: 216 to 224 ° C. Specific rotation: [α] _D ²⁵ = −68.1 ° (c = 1.1, D
MSO) IR (KBr) cm ^-1 : 1680, 1620, 1550, 1230

Example 2 (1) (S) -4-diphenylmethyl-1- (3-hydroxy-2-t-butoxycarbonylamino) propionylpiperidine Nt-butoxycarbonyl-O-tetrahydropyranyl-L- 781 mg of the title compound (1) was obtained in the same manner as (1) of Example 1 using 673 mg of serine and 4-diphenylmethylpiperidine instead of 1-benzhydrylpiperazine. Yield: 54%

NMR (CDCl ₃ ) δ: 1.0 to 1.2 (2H,
m), 1.43 (9H, s), 1.5 ~ 1.7 (2H, m), 2.2 ~ 2.4 (1H, m), 2.
56 (1H, bt), 2.8 ~ 3.1 (2H, m), 3.44 (1H, bd), 3.6 ~ 3.8
(2H, m), 3.9 ~ 4.1 (1H, m), 4.4 ~ 4.7 (2H, m), 5.70 (1H, b
d), 7.0-7.3 (10H, m)

(2) (S) -4-diphenylmethyl-1
-(3-mesyloxy-2-t-butoxycarbonylamino) propionylpiperidine Using 778 mg of the compound (1), (2) of Example 1
916 mg of the title compound (2) was obtained in the same manner as in the above. Yield: 100%

NMR (CDCl ₃ ) δ: 1.0 to 1.3 (2H,
m), 1.43 (9H, s), 1.6 ~ 1.7 (2H, m), 2.2 ~ 2.5 (1H, m), 2.
60 (1H, bt), 2.9-3.1 (1H, m), 3.00 (3H, s), 3.47 (1H, d
d, J = 8.6Hz, 7.1Hz), 3.8 ~ 4.0 (1H, m), 4.1 ~ 4.4 (2H, m),
4.49 (1H, bd), 4.8 ~ 5.0 (1H, m), 5.49 (1H, bd), 6.9 ~
7.3 (10H, m)

(3) (R) -4-diphenylmethyl-1
-[3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperidine Using 916 mg of the above compound (2), ethyl 2-mercaptonicotinate instead of methyl 2-mercaptonicotinate Was used and in the same manner as in Example 1, (3), 887 mg of the title compound (3) was obtained. Yield: 83%

NMR (CDCl ₃ ) δ: 1.0 to 1.3 (2H,
m), 1.3 ~ 1.5 (12H, m), 1.5 ~ 1.7 (2H, m), 2.2 ~ 2.5 (1
H, m), 2.55 (1H, bt), 2.9-3.2 (2H, m), 3.4-3.7 (2H,
m), 4.2 to 4.6 (4H, m), 4.9 to 5.1 (1H, m), 5.43, 5.47 (total
1H, bd each), 6.97, 6.99 (Total 1H, dd, J = 7.9Hz, 5.0 each
Hz, J = 7.9Hz, 5.0Hz), 7.1 to 7.3 (10H, m), 8.14, 8.16 (total
1H, dd, J = 7.9Hz, 1.7Hz, J = 7.9Hz, 1.7Hz respectively), 8.31,8.37
(Total 1H, dd, J = 5.0Hz, 1.7Hz, J = 5.0Hz, 1.7Hz respectively)

(4) (R) -1- [2-amino-3-
(3-ethoxycarbonylpyridin-2-yl) thio]
Propionyl-4-diphenylmethylpiperidine Using 887 mg of the above compound (3), (4) of Example 1
In the same manner as in the above, 738 mg of the title compound (4) was obtained. Yield: 100%

NMR (CDCl ₃ ) δ: 1.0 to 1.3 (2H,
m), 1.41, 1.43 (total 3H, t respectively, J = 7.1Hz, J = 7.1Hz), 1.5
~ 1.7 (2H, m), 1.77 (2H, bs), 2.3 ~ 2.5 (1H, m), 2.5 ~ 2.
7 (1H, m), 2.83 (1H, dd, J = 13.6Hz, 9.3Hz), 2.9 ~ 3.1 (1H, m
m), 3.47 (1H, d, J = 10.7Hz), 3.64 (1H, ddd, J = 13.6Hz, 3.9
Hz, 3.9Hz), 4.0 ~ 4.1 (1H, m), 4.2 ~ 4.5 (3H, m), 4.5 ~
4.7 (1H, m), 6.97,6.99 (Total 1H, dd, J = 7.9Hz, 4.6Hz, J each
= 7.9Hz, 4.6Hz), 7.1 ~ 7.3 (10H, m), 8.17 (1H, bd), 8.2
6,8.34 (Total 1H, dd, J = 4.6Hz, 1.4Hz, J = 4.6Hz, 1.4H respectively
z)

(5) (R) -4-diphenylmethyl-1
-[3- (3-Ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperidine Using 738 mg of the above compound (4), (5) of Example 1
865 mg of the title compound (5) was obtained in the same manner as in the above. Yield: 91%

NMR (CDCl ₃ + CD ₃ OD) δ:
1.0 ~ 1.3 (2H, m), 1.35,1.37 (Total 3H, each t, J = 7.2Hz, J =
7.2Hz), 1.5 to 1.8 (2H, m), 2.2 to 2.5 (1H, m), 2.62 (1H, b
t), 3.11 (1H, bt), 3.3 to 3.5 (2H, m), 3.65 (1H, ddd, J =
13.4Hz, 12.5Hz, 5.0Hz), 4.2 to 4.6 (2H, m), 4.33, 4.37 (total 2H, q, J = 7.2Hz, J = 7.2Hz), 5.5 to 5.7 (1H, m), 6.92
(1H, s), 7.03,7.04 (Total 1H, each dd, J = 7.8Hz, 5.0Hz, J =
7.8Hz, 5.0Hz), 7.1 ~ 7.4 (12H, m), 7.58 (1H, d, J = 7.2Hz),
7.64 (1H, d, J = 7.2Hz), 8.17,8.21 (total 1H, each dd, J = 7.8
Hz, 1.8Hz, J = 7.8Hz, 1.8Hz), 8.42,8.48 (1H in total, d each
d, J = 5.0Hz, 1.8Hz, J = 5.0Hz, 1.8Hz), 9.59 (1H, bs)

(6) (R) -4-diphenylmethyl-1
-[3- (3-carboxypyridin-2-yl) thio-
2- (Indol-2-yl) carbonylamino] propionylpiperidine Using 323 mg of the above compound (5), (6) of Example 1
307 mg of the title compound (6) was obtained in the same manner as in the above. Yield: 99%

IR (KBr) cm ^-1 : 3430, 1700, 162
0, 1580, 1560 NMR (CDCl ₃ ) δ: 1.0 to 1.4 (2H, m), 1.6 to 1.8
(2H, m), 2.3 to 2.6 (1H, m), 2.6 to 2.8 (1H, m), 2.88 (1H, b
t), 3.0-3.4 (1H, m), 3.51 (1H, dd, J = 12.6Hz, 12.6Hz),
3.96 (1H, bd), 4.5 ~ 4.8 (2H, m), 5.5 ~ 5.6 (1H, m), 6.9
~ 7.4 (14H, m), 7.38 (1H, d, J = 7.2Hz), 7.52 (1H, d, J = 7.2H)
z), 7.67 (1H, dd, J = 7.2Hz, 7.2Hz), 8.06 (1H, bd), 8.4 ~ 8.
5 (1H, m), 11.01 (1H, bs) Specific rotation: [α] _D ²⁵ = −57.9 ° (c = 1.2, D
MSO)

Example 3 (1) (R) -1- [2- (5-chloroindole-2)
-Yl) carbonylamino-3-ethoxycarbonylpyridin-2-yl) thio] propionyl-4-diphenylmethylpiperazine (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2 as a raw material -(T-butoxycarbonylamino)] propionyl-4-diphenylmethylpiperazine (2.00 g) and 5-chloroindole-2-carboxylic acid in place of indole-2-carboxylic acid. In the same manner as in (5), 1.76 g of the title compound (1) was obtained. Yield: 78%

NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.
2Hz), 2.43 (4H, bs), 3.3 ~ 3.5 (1H, m), 3.6 ~ 4.0 (5H, m),
4.22 (1H, s), 4.30 (2H, q, J = 7.2Hz), 5.5 ~ 5.7 (1H, m), 6.7
8 (1H, s), 6.9 ~ 7.5 (14H, m), 7.99 (1H, d, J = 7.8Hz), 8.20
(1H, dd, J = 7.4Hz, 1.8Hz), 8.45 (1H, dd, J = 5.4Hz, 1.8Hz),
9.89 (1H, s)

(2) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-chloroindol-2-yl) carbonylamino] propionyl-4
-Diphenylmethylpiperazine Using 1.50 g of the above compound (1) as a starting material, 1.23 g of the title compound (2) in the same manner as in (6) of Example 1.
I got Yield: 86%

IR (KBr) cm ^-1 : 1710, 1630, 155
0, 1450 NMR (DMSO-d ₆ ) δ: 2.30 (4H, bs), 3.1 to 4.0
(6H, m), 4.30 (1H, s), 5.1 to 5.4 (1H, m), 7.1 to 7.6 (14H,
m), 7.78 (1H, bs), 8.12 (1H, bd), 8.55 (1H, bd), 9.00 (1
H, d, J = 8.2Hz), 11.80 (1H, s) Specific rotation: [α] _D ²⁵ = -66.5 ° (c = 1.0, D
MSO)

Example 4 (R) -4-diphenylmethyl-1- [2- (indol-2-yl) carbonylamino-3- (3-methoxycarbonylmethyloxycarbonylpyridin-2-yl) thio] propionylpiperazine As a raw material, (R) -4-diphenylmethyl-1- [3-
(3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine (compound (6) of Example 1) (5.00 g) and methyl bromoacetate (1.50 g) were used. In the same manner as in Example 1, (3), 4.78 g of the title compound was obtained. Yield: 86
%

IR (KBr) cm ^-1 : 1760, 1720, 163
0, 1550 NMR (CDCl ₃ ) δ: 2.2 to 2.5 (4H, m), 3.3 to 4.0
(6H, m), 3.60, 3.79 (total 3H, each s), 4.20, 4.27 (total 1H, each s), 4.77,4.84,4.94,5.10 (total 2H, each d, J
= 8.3Hz, J = 8.3Hz, 14.8 Hz, 14.8Hz), 5.3 ~ 5.7 (1H, m),
6.8 ~ 7.5 (15H, m), 7.54,7.60 (1H in total, d, J = 7.8Hz each,
7.8Hz), 7.86,7.90 (total 1H, d, J = 8.8Hz, 8.8Hz respectively),
8.2 to 8.3 (1H, m), 8.4 to 8.5 (1H, m), 10.00 (1H, bs) Specific rotation: [α] _D ²⁵ = -56.7 ° (c = 1.2, D
MSO)

Example 5 (R) -1- [3- (3-carboxypyridin-2-yl) thio] -2- (1-methoxycarbonylethylindol-2-yl) carbonylamino] propionyl-
4-diphenylmethylpiperazine (R) -4-diphenylmethyl-1- [3-
(3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine (compound (6) of Example 1) (5.00 g) and methyl acrylate (0.90 g) were used. In the same manner as in Example 1, (3), 1.10 g of the title compound was obtained. Yield: 19
%

IR (KBr) cm ^-1 : 1730, 1640, 154
0, 1450 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 2.6 to
2.8 (2H, m), 3.2 to 3.4 (1H, m), 3.4 to 4.0 (5H, m), 3.48 (3
H, s), 4.34 (1H, s), 4.6 ~ 4.8 (2H, m), 5.1 ~ 5.3 (1H, m),
7.1 ~ 7.5 (14H, m), 7.54 (1H, d, J = 8.8Hz), 7.66 (1H, d, J =
7.0Hz), 8.1 ~ 8.3 (1H, m), 8.4 ~ 8.6 (1H, m), 8.85 (1H, d, J
= 7.9 Hz) Specific rotation: [α] _D ²⁵ = -58.2 ° (c = 0.9, D
MSO)

Example 6 (1) (R) -4-diphenylmethyl-1- [3- (3
-Ethoxycarbonylpyridin-2-yl) thio-2-
(5-methoxyindol-2-yl) carbonylamino] propionylpiperazine (R) -4-diphenylmethyl-1- [3-
(3-ethoxycarbonylpyridin-2-yl) thio-
2-t-butoxycarbonylamino] propionylpiperazine (2.50 g) and 5-methoxyindole-2-carboxylic acid in place of indole-2-carboxylic acid, as in (4) and (5) of Example 1 2.40 g of the title compound (1) was obtained by the above method. Yield: 86%

NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.
3Hz), 2.40 (4H, bs), 3.3 ~ 3.5 (1H, m), 3.6 ~ 4.0 (5H, m),
3.81 (3H, s), 4.21 (1H, s), 4.32 (2H, q, J = 7.3Hz), 5.5 ~
5.7 (1H, m), 6.7 to 6.9 (2H, m), 6.9 to 7.1 (2H, m), 7.1 to 7.5
(11H, m), 7.65 (1H, d, J = 7.8Hz), 8.18 (1H, dd, J = 8.0Hz, 1.
8Hz), 8.49 (1H, dd, J = 5.6Hz, 1.8Hz), 9.54 (1H, bs)

(2) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-methoxyindol-2-yl) carbonylamino] propionyl-
4-Diphenylmethylpiperazine Using 2.00 g of the above compound (1) as a raw material, 1.62 g of the title compound (2) in the same manner as in (6) of Example 1.
I got Yield: 85%

IR (KBr) cm ^-1 : 1700, 1630, 154
0, 1230 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.2 to
3.8 (6H, m), 3.77 (3H, s), 4.28 (1H, s), 5.1 to 5.3 (1H, m),
6.85 (1H, dd, J = 8.8Hz, 2.2Hz), 7.1 ~ 7.5 (14H, m), 8.21
(1H, dd, J = 8.8Hz, 1.8Hz), 8.54 (1H, dd, J = 5.2Hz, 1.8Hz),
8.79 (1H, d, J = 8.5 Hz), 11.39 (1H, s) Specific rotation: [α] _D ²⁵ = −57.2 ° (c = 1.1, D
MSO)

Example 7 (1) (S) -4-bis (4-methoxyphenyl) methyl-1- (3-hydroxy-2-t-butoxycarbonylamino] propionylpiperazine Nt-butoxycarbonyl-O- From 578 mg of tetrahydropyranyl-L-serine, 1-bis (4-methoxyphenyl) is used instead of 1-benzhydrylpiperazine.
Using methyl piperazine, 649 mg of the title compound (1) was obtained in the same manner as in Example 1, (1). Yield: 65%

NMR (CDCl ₃ ) δ: 1.41 (9H, s), 2.
36 (4H, bs), 3.58 (4H, bs), 3.72 (1H, bs), 3.74 (6H, s),
4.15 (1H, s), 4.5 ~ 4.7 (1H, m), 5.75 (1H, bd), 6.81 (4H, d,
J = 8.5Hz), 7.27 (4H, d, J = 8.5Hz)

(2) (R) -4-bis (4-methoxyphenyl) methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperazine From 649 mg of compound (1), (2)
In the same manner as in (3), using ethyl 2-mercaptonicotinate instead of methyl 2-mercaptonicotinate,
779 mg of the title compound (2) was obtained. Yield: 90%

NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.
39 (3H, t, J = 7.1Hz), 2.2 ~ 2.5 (4H, m), 3.0 ~ 3.2 (1H, m),
3.5 to 3.9 (5H, m), 3.75 (6H, s), 4.16 (1H, s), 4.38 (2H, q, J
= 7.1Hz), 4.9 ~ 5.1 (1H, m), 5.49 (1H, bd), 6.82 (4H, d, J =
8.5Hz), 7.03 (1H, dd, J = 7.8Hz, 4.6Hz), 7.29 (4H, d, J = 8.5
Hz), 8.20 (1H, dd, J = 7.8Hz, 1.8Hz), 8.40 (1H, dd, J = 4.6H
(z, 1.8Hz)

(3) (R) -4-bis (4-methoxyphenyl) methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino Propionyl piperazine Using 779 mg of the above compound (2), 73 g of the title compound (3) was obtained in the same manner as in (4) and (5) of Example 1.
8 mg were obtained. Yield: 89%

NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.
2Hz), 2.2 ~ 2.5 (4H, m), 3.3 ~ 3.5 (1H, m), 3.6 ~ 3.9 (5
H, m), 3.75 (6H, s), 4.14 (1H, s), 4.32 (2H, q, J = 7.2Hz),
5.5 ~ 5.7 (1H, m), 6.81 (4H, d, J = 8.5Hz), 6.88 (1H, s), 7.
0 ~ 7.3 (4H, m), 7.27 (4H, d, J = 8.5Hz), 7.57 (1H, d, J = 7.6H
z), 7.71 (1H, bd), 8.18 (1H, dd, J = 7.8Hz, 1.8Hz), 8.46 (1
(H, dd, J = 4.6Hz, 1.8Hz), 9.32 (1H, bs)

(4) (R) -4-bis (4-methoxyphenyl) methyl-1- [3- (3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] Propionylpiperazine Using the above compound (3) (700 mg), Example 1 (6)
670 mg of the title compound (4) was obtained in the same manner as in the above. Yield: 97%

IR (KBr) cm ^-1 : 1700, 1630, 155
0, 1510 NMR (DMSO-d 6) δ: 2.28 (4H, bs), 3.2~3.4
(1H, m), 3.5 to 3.9 (5H, m), 3.71 (6H, s), 4.19 (1H, s), 5.
1 ~ 5.3 (1H, m), 6.7 ~ 6.9 (5H, m), 7.04 (1H, dd, J = 7.6Hz,
7.6Hz), 7.1 to 7.3 (6H, m), 7.42 (1H, d, J = 7.6Hz), 7.64
(1H, d, J = 7.6Hz), 8.22 (1H, dd, J = 7.8Hz, 1.8Hz), 8.54 (1H,
dd, J = 4.6Hz, 1.8Hz), 8.82 (1H, d, J = 7.7Hz), 11.54 (1H, b
s) Specific rotation: [α] _D ²⁵ = −39.8 ° (c = 1.3, D
MSO)

Example 8 (1) (S) -4-bis (2-pyridyl) methyl-1-
(3-Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine 1-benzhi from 407 mg of Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine in the same manner as (1) of Example 1. 1 instead of drill piperazine
Using -bis (2-pyridyl) methylpiperidine, 343 mg of the title compound (1) was obtained. Yield: 55%

NMR (CDCl ₃ ) δ: 1.40 (9H, s), 2.
04 (4H, bs), 3.5-3.8 (7H, m), 4.5-4.7 (1H, m), 4.66 (1
H, s), 5.76 (1H, bd), 7.1 ~ 7.2 (2H, m), 7.5 ~ 7.7 (4H,
m), 8.55 (2H, d, J = 4.9Hz)

(2) (S) -4-bis (2-pyridyl)
Methyl-1- (3-mesyloxy-2-t-butoxycarbonylamino) propionylpiperazine 381 mg of the title compound (2) was obtained from 343 mg of the compound (1) in the same manner as in (2) of Example 1. Yield: 94%

NMR (CDCl ₃ ) δ: 1.42 (9H, s),
2.4 to 2.6 (4H, m), 3.03 (3H, s), 3.6 to 3.8 (4H, m), 4.2 to
4.4 (2H, m), 4.68 (1H, s), 4.8 ~ 5.0 (1H, m), 5.54 (1H, b
d), 7.1 ~ 7.2 (2H, m), 7.5 ~ 7.7 (4H, m), 8.5 ~ 8.6 (2H, m
m)

(3) (R) -4-bis (2-pyridyl)
Methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperazine From 381 mg of the above compound (2), in the same manner as in (3) of Example 1, Using methyl 2-mercaptonicotinate in place of methyl 2-mercaptonicotinate and sodium hydride in place of potassium carbonate, the title compound (3)
437 mg was obtained. Yield: 98%

NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.
40 (3H, t, J = 7.2Hz), 2.3 ~ 2.6 (4H, m), 3.0 ~ 3.2 (1H, m),
3.5 ~ 4.0 (5H, m), 4.38 (2H, q, J = 7.2Hz), 4.67 (1H, s), 4.
9 ~ 5.1 (1H, m), 5.48 (1H, bd), 7.05 (1H, dd, J = 7.8Hz, 4.6H
z), 7.2-7.3 (1H, m), 7.5-7.7 (4H, m), 8.20 (1H, dd, J =
7.8Hz, 1.8Hz), 8.40 (1H, dd, J = 4.6Hz, 1.8Hz), 8.54 (2H,
d, J = 4.9Hz)

(4) (R) -4-bis (2-pyridyl)
Methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine From 437 mg of the above compound (3), 4N hydrogen chloride (ethyl acetate solution) (4) of Example 1 using indole-2-carboxylic acid instead of trifluoroacetic acid instead of
413 mg of the title compound (4) was obtained in the same manner as in (5).
Obtained. Yield: 88%

NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.
2Hz), 2.47 (4H, bs), 3.4 to 3.6 (1H, m), 3.6 to 4.0 (5H, m),
4.32 (2H, q, J = 7.2Hz), 4.66 (1H, s), 5.5 ~ 5.7 (1H, m), 6.8
9 (1H, s), 7.0 ~ 7.2 (5H, m), 7.26 (1H, d, J = 6.1Hz), 7.5 ~ 7.
7 (5H, m), 7.84 (1H, bd), 8.17 (1H, dd, J = 7.8Hz, 1.8Hz), 8.
45 (1H, dd, J = 4.6Hz, 1.8Hz), 8.54 (2H, d, J = 4.9Hz), 9.86
(1H, bs)

(5) (R) -4-bis (2-pyridyl)
Methyl-1- [3- (3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine Same as (6) in Example 1 from 374 mg of the above compound (4). 280 mg of the title compound (5) was obtained by the method described above. Yield: 78%

IR (KBr) cm ^-1 : 1700, 1630, 155
0, 1430 NMR (DMSO-d 6) δ: 2.2~2.6 (4H, bs), 3.1
~ 3.9 (6H, m), 4.7 ~ 4.9 (1H, bs), 5.1 ~ 5.3 (1H, m), 7.0
~ 7.3 (6H, m), 7.41 (1H, d, J = 8.2Hz), 7.5 ~ 7.7 (3H, m),
7.7 ~ 7.8 (2H, m), 8.21 (1H, dd, J = 7.8Hz, 1.8Hz), 8.4 ~ 8.5
(2H, m), 8.55 (1H, dd, J = 4.6Hz, 1.8Hz), 8.85 (1H, d, J = 8.2
Hz), 11.54 (1H, bs) Specific rotation: [α] _D ²⁵ = -61.1 ° (c = 0.8, D
MSO)

Example 9 (1) (R) -4-diphenylmethyl-1- [3- (2
-Methoxycarbonylphenyl) thio-2-t-butoxycarbonylamino] propionylpiperazine (S) -4-diphenylmethyl-1- (3-hydroxy-2-t-butoxycarbonylamino) propionylpiperazine ((1 )) From 1.32 g, 868 mg of the title compound (1) was obtained in the same manner as in (2) and (3) of Example 1, except that methyl thiosalicylate was used instead of methyl 2-mercaptonicotinate. Yield: 49%

NMR (CDCl ₃ ) δ: 1.42 (9H, s),
2.1 ~ 2.4 (4H, m), 3.1 ~ 3.3 (2H, m), 3.3 ~ 3.5 (2H, m), 3.
5 to 3.7 (2H, m), 3.92 (3H, s), 4.15 (1H, s), 4.7 to 4.9 (1
H, m), 5.52 (1H, bd), 7.1 ~ 7.6 (13H, m), 7.8 ~ 8.0 (1H,
m)

(2) (R) -4-diphenylmethyl-1
-[2- (indol-2-yl) carbonylamino-
3- (2-Methoxycarbonylphenyl) thio] propionylpiperazine From the above compound (1) (289 mg), Example 1 (4),
247 mg of the title compound (2) was obtained in the same manner as in (5).
Obtained. Yield: 79%

NMR (CDCl ₃ ) δ: 2.1 to 2.4 (4H,
m), 3.3 to 3.5 (4H, m), 3.5 to 3.7 (2H, m), 3.90 (3H, s), 4.1
3 (1H, s), 5.3 ~ 5.5 (1H, m), 6.98 (1H, s), 7.0 ~ 7.4 (15
H, m), 7.5 to 7.7 (3H, m), 7.89 (1H, d, J = 7.6Hz)

(3) (R) -1- [3- (2-carboxyphenyl) thio-2- (indol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine From the above compound (2), 148 mg, 119 mg of the title compound (3) was obtained in the same manner as in (6) of Example 1. Yield: 82%

IR (KBr) cm ^-1 : 1690, 1630, 154
0, 1450 NMR (CDCl ₃ ) δ: 2.1 to 2.4 (4H, m), 2.9 to 3.1
(2H, m), 3.2 ~ 3.4 (4H, m), 4.15 (1H, s), 5.2 ~ 5.4 (1H,
m), 6.9-7.4 (17H, m), 7.5-7.7 (2H, m), 8.6-8.8 (1H,
m), 11.34 (1H, bs) Specific rotation: [α] _D ²⁵ = −37.2 ° (c = 0.7, D
MSO)

Example 10 (1) (S) -4-bis (4-fluorophenyl) methyl-1- (3-hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Instead of 1-diphenylmethylpiperazine as a raw material 139 mg of the title compound (1) was obtained in the same manner as in Example 1, (1) using 1-bis (4-fluorophenyl) methylpiperazine. Yield: 56%

NMR (CDCl ₃ ) δ: 1.40 (9H, s),
2.3 to 2.5 (4H, m), 3.4 to 3.8 (7H, m), 4.23 (1H, s), 4.5 to
4.7 (1H, m), 5.6 ~ 5.8 (1H, bd), 6.99 (4H, dd, J = 8.6Hz, 8.6H
z), 7.2-7.4 (4H, m)

(2) (R) -4-bis (4-fluorophenyl) methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperazine Example 1 using 139 mg of the above compound (1)
In the same manner as in (2) and (3) above, the title compound (2) 17
7 mg were obtained. Yield: 86%

NMR (CDCl ₃ ) δ: 1.38 (9H, s),
1.1 ~ 1.5 (3H, m), 2.2 ~ 2.5 (4H, m), 3.4 ~ 4.0 (6H, m), 4.2
2 (1H, s), 5.49 (1H, bd), 6.9 ~ 7.1 (5H, m), 7.2 ~ 7.4 (4
H, m), 8.1 ~ 8.3 (1H, m), 8.3 ~ 8.5 (1H, m)

(3) (R) -4-bis (4-fluorophenyl) methyl-1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino Propionylpiperazine Using 177 mg of the above compound (2) as a starting material, the title compound (3) 1 was prepared in the same manner as in (4) and (5) of Example 1.
43 mg were obtained. Yield: 76%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 9.
2Hz), 2.1 ~ 2.5 (4H, m), 3.3 ~ 3.9 (6H, m), 4.0 ~ 4.2 (2
H, m), 4.22 (1H, s), 5.4 ~ 5.6 (1H, m), 6.8 ~ 7.4 (13H,
m), 7.5 ~ 7.7 (2H, m), 8.28 (1H, d, J = 7.1Hz), 8.4 ~ 8.5
(1H, m), 9.52 (1H, bs)

(4) (R) -4-bis (4-fluorophenyl) methyl-1- [3- (3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] Example 1 Using 142 mg of the above compound (3) as a raw material for propionylpiperazine
In a similar manner to (6), 110 mg of the title compound (4) was obtained. Yield: 81%

IR (KBr) cm ^-1 : 1630, 1550, 145
0, 1220 NMR (CDCl ₃ ) δ: 2.3 to 2.7 (4H, m), 3.5 to 4.1
(6H, m), 4.21 (1H, s), 5.5 ~ 5.6 (1H, m), 7.0 ~ 7.7 (15H,
m), 8.10 (1H, d, J = 7.2Hz), 8.4 ~ 8.5 (1H, m), 11.08 (1H, b
s) Specific rotation: [α] _D ²⁵ = -60.7 ° (c = 1.0, D
MSO)

Example 11 (1) (R) -4-diphenylmethyl-1- (3-hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Nt-butoxycarbonyl-O-tetrahydropyranyl- Using 411 mg of D-serine, 343 mg of the title compound (1) was obtained in the same manner as in (1) of Example 1. Yield: 55%

NMR (CDCl ₃ ) δ: 1.21 (9H, s),
2.3 to 2.4 (4H, m), 3.4 to 3.8 (7H, m), 4.21 (1H, s), 4.5 to
4.6 (1H, m), 5.55 (1H, d, J = 7.1Hz), 7.1 ~ 7.5 (11H, m)

(2) (S) -4-diphenylmethyl-1
-[3- (3-Methoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionylpiperazine Using the above compound (1) (500 mg) as a raw material, In a similar manner, the title compound (2) 6
12 mg were obtained. Yield: 90%

NMR (CDCl ₃ ) δ: 1.34 (9H, s),
2.2 to 2.5 (4H, m), 3.0 to 3.2 (2H, m), 3.4 to 3.7 (4H, m), 3.
88 (3H, s), 4.20 (1H, s), 4.8 ~ 5.0 (1H, m), 5.43 (1H, d, J =
9.2Hz), 6.9-7.4 (11H, m), 7.1-7.2 (1H, m), 7.3-
7.4 (1H, m), 7.5 ~ 7.6 (1H, m)

(3) (S) -4-diphenylmethyl-1
-[2- (indol-2-yl) carbonylamino-
3- (3-Methoxycarbonylpyridin-2-yl) thio] propionylpiperazine Using 612 mg of the above compound (2) as a starting material, the title compound (3) 5 was prepared in the same manner as (4) and (5) of Example 1.
98 mg were obtained. Yield: 91%

NMR (CDCl ₃ ) δ: 2.2 to 2.6 (4H,
m), 3.2 to 3.7 (6H, m), 3.59 (3H, s), 4.00 (1H, s), 5.3 to
5.6 (1H, m), 6.6 to 7.2 (16H, m), 7.30 (1H, d, J = 7.9Hz),
7.7 to 7.9 (2H, m), 8.1 to 8.3 (1H, m)

(4) (S) -4-diphenylmethyl-1
-[3- (3-carboxypyridin-2-yl) thio-
2- (Indol-2-yl) carbonylamino] propionylpiperazine Using 335 mg of the above compound (3) as a raw material, 294 mg of the title compound (4) in the same manner as in (6) of Example 1.
I got Yield: 90%

IR (KBr) cm ^-1 : 1630, 1550, 1450 NMR (CD ₃ OD) δ: 2.1 to 2.6 (4H, m), 3.2 to 4.0
(7H, m), 4.2 ~ 4.3 (1H, m), 5.4 ~ 5.6 (1H, m), 6.98 (1H, m
s), 6.9 to 7.1 (1H, m), 7.1 to 7.5 (13H, m), 7.58 (1H, d, J =
8.9Hz), 8.25 (1H, dd, J = 10.0Hz, 8.0Hz), 7.4-7.5 (1
H, m) Specific rotation: [α] _D ²⁵ = + 57.1 ° (c = 0.8, D
MSO)

Example 12 (1) (R) -4-diphenylmethyl-1- [3- (3
-Ethoxycarbonylpyridin-2-yl) thio-2-
(5-Hydroxyindol-2-yl) carbonylamino] propionylpiperazine (R) -4-diphenylmethyl-1- [3-
(3-ethoxycarbonylpyridin-2-yl) thio-
2-t-butoxycarbonylamino] propionylpiperazine (516 mg) and 5-hydroxyindole-2-carboxylic acid in place of indole-2-carboxylic acid as in (4), (5) of Example 1 472 mg of the title compound (1) was obtained by the method described above. Yield: 53%

NMR (CD ₃ OD) δ: 1.32 (3H, t, J = 7.
2Hz), 2.0 ~ 2.5 (4H, m), 3.1 ~ 4.0 (7H, m), 4.18 (2H, q, J
= 7.2Hz), 5.32 (1H, s), 5.3 ~ 5.6 (1H, m), 6.5 ~ 7.5 (14
H, m), 8.0 ~ 8.2 (1H, m), 8.2 ~ 8.5 (1H, m), 10.10 (1H, b
s)

(2) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-hydroxyindol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine 307 mg of the title compound (2) in the same manner as in (6) of Example 1 using 310 mg of the above compound (1).
I got Yield: 95%

IR (KBr) cm ^-1 : 1630, 1550, 1450 NMR (CD ₃ OD) δ: 2.2 to 2.6 (4H, m), 3.4 to 4.0
(6H, m), 5.35 (1H, s), 5.4 ~ 5.6 (1H, m), 6.8 ~ 6.9 (1H,
m), 6.98 (1H, s), 7.0-7.5 (15H, m), 8.2-8.3 (1H, m),
8.3 to 8.5 (1H, m) Specific rotation: [α] _D ²⁵ = −64.0 ° (c = 0.6, D
MSO)

Example 13 (1) (S) -1- (3-hydroxy-2-t-butoxycarbonylamino) propionyl-4-isopropylpiperazine Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine 434 mg, 1-isopropylpiperazine 230 mg, 1-hydroxybenzotriazole 27
5 mg was dissolved in 5 ml of dichloromethane, and 345 mg of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride was added thereto, followed by stirring at room temperature for 14 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 520 mg of a residue. 4 ml of tetrahydrofuran and 4 ml of 1N hydrochloric acid were added to the residue, and the mixture was stirred for 1 hour. The reaction solution was alkalified by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate (10 ml × 3), and washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 416 mg of a residue. This was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 9/1) to obtain 251 mg of the title compound (1). Yield: 53%

NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.
6Hz), 1.44 (9H, s), 2.4 ~ 2.6 (4H, m), 2.72 (1H, sep, J = 6.
6Hz), 3.5-3.7 (4H, m), 3.7-3.8 (2H, m), 3.84 (1H, b
s), 4.6-4.8 (1H, m), 5.84 (1H, bd)

(2) (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionyl-4-isopropylpiperazine (i) Compound (1) 251 mg and 178 mg of triethylamine were dissolved in 2 ml of dichloromethane, and a dichloromethane solution of 183 mg of methanesulfonyl chloride was added dropwise at −10 ° C. over 10 minutes, and then stirred for 15 minutes. Dichloromethane was added to the reaction solution, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 310 mg of a residue. (Ii) 1 ml of dimethylformamide was added to 63 mg of sodium hydride (60% content), and a solution of 289 mg of ethyl 2-mercaptonicotinate in dimethylformamide (1 ml) was added dropwise at room temperature over 10 minutes, followed by stirring for 30 minutes. . This solution was added dropwise to a solution of the above residue in dimethylformamide (2 ml) at room temperature over 10 minutes, and then stirred for 3 hours. Water and ethyl acetate were added to the reaction solution, extracted with ethyl acetate (10 ml × 3), washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 669 mg of a residue. This was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 9/1) to obtain 351 mg of the title compound (2). Yield: 91%

NMR (CDCl ₃ ) δ: 1.04 (6H, d, J = 6.
3Hz), 1.38 (9H, s), 1.40 (3H, t, J = 7.1Hz), 2.4 ~ 2.6 (4H,
m), 2.71 (1H, sep, J = 6.3Hz), 3.0 ~ 3.2 (1H, m), 3.5 ~ 3.
7 (4H, m), 3.7 ~ 3.9 (1H, m), 4.38 (2H, q, J = 7.1Hz), 4.9 ~
5.1 (1H, m), 5.50 (1H, bd), 7.09 (1H, dd, J = 7.8Hz, 4.6Hz),
8.23 (1H, dd, J = 7.8Hz, 1.7Hz), 8.52 (1H, dd, J = 4.6Hz, 1.7
Hz)

(3) (R) -1- [2- (indole-
2-yl) carbonylamino-3- (3-ethoxycarbonylpyridin-2-yl) thio] propionyl-4-
Isopropyl piperazine To 351 mg of the above compound (2), 5 ml of 4N hydrogen chloride (ethyl acetate solution) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate (10 ml × 3), and washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 279 mg of a residue. This was dissolved in 5 ml of dichloromethane, and indole-2-carboxylic acid 12 was dissolved.
9 mg, 1-hydroxybenzotriazole 123 m
g, 1-ethyl-3- (3-dimethylaminopropyl)
154 mg of carbodiimide hydrochloride were sequentially added, and 1
Stir for 5 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 411 mg of a residue. This was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 9/1) to obtain 354 mg of the title compound (3). Yield: 92%

NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.
4Hz), 1.35 (3H, t, J = 7.0Hz), 2.50 (4H, bs), 2.68 (1H, se
(p, J = 6.4Hz), 3.4-3.6 (1H, m), 3.6-3.9 (5H, m), 4.34 (2
(H, q, J = 7.0Hz), 5.6 ~ 5.8 (1H, m), 6.94 (1H, s), 7.0 ~ 7.1
(2H, m), 7.16 (1H, dd, J = 8.0Hz, 8.0Hz), 7.30 (1H, d, J = 8.0
Hz), 7.56 (1H, d, J = 8.0Hz), 7.96 (1H, d, J = 8.3Hz), 8.19 (1
H, dd, J = 7.6Hz, 1.8Hz), 8.54 (1H, dd, J = 4.6Hz, 1.8Hz), 10.
05 (1H, bs)

(4) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4-isopropylpiperazine 308 mg of the above compound (3) was added to 3 m of tetrahydrofuran.
3 ml of water, lithium hydroxide monohydrate 74m
g and 2 ml of methanol were sequentially added, followed by stirring at room temperature for 2 hours. After concentrating the reaction solution to about 4 ml, it was neutralized with a 10% aqueous citric acid solution and extracted with dichloromethane (15 ml × 3). After washing with saturated saline, drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound (4) 211m
g was obtained. Yield: 72%

IR (KBr) cm ^-1 : 1720, 1630, 155
0, 1450 NMR (DMSO-d ₆ ) δ: 1.00 (6H, d, J = 6.4 Hz),
2.4 to 2.9 (5H, m), 3.1 to 3.3 (1H, m), 3.4 to 3.6 (1H, m), 3.
6 to 3.8 (3H, m), 3.8 to 4.0 (1H, m), 5.2 to 5.4 (1H, m), 7.02
(1H, dd, J = 7.6Hz, 7.6Hz), 7.1 ~ 7.3 (3H, m), 7.42 (1H, d,
J = 8.2Hz), 7.58 (1H, d, J = 7.6Hz), 8.20 (1H, dd, J = 7.9Hz, 1.
8Hz), 8.63 (1H, dd, J = 4.9Hz, 1.8Hz), 8.87 (1H, d, J = 8.2H
z), 11.56 (1H, bs) Specific rotation: [α] _D ²⁵ = −103.9 ° (c = 1.0,
DMSO)

Example 14 (1) (S) -1- (3-Hydroxy-2-t-butoxycarbonylamino) propionyl-4- (1-butylpentyl) piperazine As a raw material, Nt-butoxycarbonyl-O- Using 4.20 g of tetrahydropyranyl-L-serine and 1- (1-butylpentyl) piperazine instead of 1-benzhydrylpiperazine, the title compound (1) was prepared in the same manner as in Example 1, (1). ) 2.96 g were obtained. Yield: 51%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H,
m), 1.1 ~ 1.4 (13H, m), 1.49 (9H, s), 2.2 ~ 2.4 (1H, m), 2.
4 to 2.6 (4H, m), 3.4 to 3.9 (6H, m), 4.5 to 4.7 (1H, m), 5.75
(1H, bd)

(2) (S) -1- (3-mesyloxy-
2-tert-butoxycarbonylamino) propionyl-4
-(1-butylpentyl) piperazine Using 2.50 g of the above compound (1) as a starting material, the title compound (2) was obtained in the same manner as in Example 13, (2) (i).
2.88 g were obtained. Yield: 96%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H,
m), 1.1 ~ 1.4 (12H, m), 1.49 (9H, s), 2.2 ~ 2.4 (1H, m), 2.
4 to 2.6 (4H, m), 3.08 (3H, s), 3.4 to 3.7 (4H, m), 4.2 to 4.4
(2H, m), 4.8 ~ 5.0 (1H, m), 5.55 (1H, bd)

(3) (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionyl-4- (1-butylpentyl) piperazine Using 2.88 g of compound (2), the title compound (3) was prepared in the same manner as in (2) (ii) of Example 13.
1.98 g were obtained. Yield: 58%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H,
m), 1.1 ~ 1.6 (15H, m), 1.40 (9H, s), 2.2 ~ 2.7 (5H, m), 3.
0-3.2 (1H, m), 3.4-3.9 (5H, m), 4.40 (2H, q, J = 7.2Hz),
4.9 ~ 5.1 (1H, m), 5.50 (1H, bd), 7.10 (1H, dd, J = 7.6Hz, 5.
2Hz), 8.22 (1H, dd, J = 7.6Hz, 1.8Hz), 8.61 (1H, dd, J = 5.2H
(z, 1.8Hz)

(4) (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionyl-4-
(1-butylpentyl) piperazine Using 1.90 g of the above compound (3) as a raw material, the title compound (4) 1.31 was obtained in the same manner as in Example 13, (3).
g was obtained. Yield: 65%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (6H,
m), 1.1 ~ 1.5 (15H, m), 2.3 ~ 2.5 (1H, m), 2.5 ~ 2.7 (4
H, m), 3.3 ~ 3.6 (1H, m), 3.6 ~ 4.0 (5H, m), 4.37 (2H, q, J =
7.2Hz), 5.5 ~ 5.7 (1H, m), 6.90 (1H, s), 7.0 ~ 7.4 (4H,
m), 7.5 to 7.8 (2H, m), 8.20 (1H, dd, J = 7.8Hz, 1.8Hz), 8.5
8 (1H, dd, J = 5.6Hz, 1.8Hz), 9.50 (1H, s)

(5) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4- (1-butylpentyl) piperazine Using 1.20 g of the above compound (4) as a starting material, the title compound (5) 1.26 was obtained in the same manner as in Example 13, (4).
g was obtained. Yield: 97%

IR (KBr) cm ^-1 : 2960, 2930, 171
0, 1630, 1550 NMR (DMSO-d ₆ ) δ: 0.8 to 1.0 (6H, m), 1.0 to
1.5 (12H, m), 2.3 to 2.7 (5H, m), 3.1 to 3.4 (1H, m), 3.4
~ 3.8 (4H, m), 3.8 ~ 4.0 (1H, m), 5.2 ~ 5.4 (1H, m), 7.0 ~
7.1 (1H, m), 7.1 to 7.3 (3H, m), 7.42 (1H, d, J = 8.2Hz), 7.6
2 (1H, d, J = 7.9Hz), 8.27 (1H, dd, J = 7.8Hz, 1.8Hz), 8.67 (1
H, dd, J = 5.4Hz, 1.8Hz), 8.85 (1H, d, J = 7.6Hz), 11.54 (1H,
s) Specific rotation: [α] _D ²⁵ = -69.2 ° (c = 1.0, D
MSO)

Example 15 (1) (S) -4-diisopropylmethyl-1- (3-
(Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine (5.60 g) was used as a raw material, and 1-diisopropylmethylpiperazine was used instead of 1-isopropylpiperazine. In the same manner as in Example 13, (1), 4.38 g of the title compound (1) was obtained. Yield: 61%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (12H,
m), 1.50 (9H, s), 1.8 ~ 2.0 (3H, m), 2.6 ~ 2.8 (4H, m), 3.
4 to 3.7 (5H, m), 3.7 to 3.9 (2H, m), 4.5 to 4.7 (1H, m), 5.73
(1H, bd)

(2) (R) -4-diisopropylmethyl-1- [3- (3-ethoxycarbonylpyridine-2-
Yl) thio-2-t-butoxycarbonylamino] propionylpiperazine Using 4.00 g of the above compound (1) as a starting material, the title compound (2) 3.40 was obtained in the same manner as in Example 13, (2).
g was obtained. Yield: 59%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (12H,
m), 1.40 (9H, s), 1.3 ~ 1.5 (3H, m), 1.70 (1H, bs), 1.8 ~
2.0 (2H, m), 2.6 ~ 2.9 (4H, m), 3.0 ~ 3.3 (1H, m), 3.4 ~ 3.
9 (5H, m), 4.40 (2H, q, J = 7.4Hz), 4.9 ~ 5.1 (1H, m), 5.50 (1
H, bd), 7.0-7.2 (1H, m), 8.2-8.4 (1H, m), 8.5-8.6 (1
H, m)

(3) (R) -4-diisopropylmethyl-1- [3- (3-ethoxycarbonylpyridine-2-
Yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine Using 3.00 g of the compound (2) as a starting material, the title compound (3) .2. 70
g was obtained. Yield: 83%

NMR (CDCl ₃ ) δ: 0.8 to 1.0 (12H,
m), 1.39 (3H, t, J = 7.6Hz), 1.8 ~ 2.0 (3H, m), 2.6 ~ 2.8
(4H, m), 3.4 ~ 3.9 (6H, m), 4.36 (2H, q, J = 7.6Hz), 5.5 ~
5.7 (1H, m), 6.90 (1H, s), 7.0-7.4 (5H, m), 7.60 (1H, d, J
= 7.8Hz), 8.2-8.3 (1H, m), 8.5-8.6 (1H, m), 9.49 (1H, b
s)

(4) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4-diisopropylmethylpiperazine Using 2.50 g of the above compound (3) as a starting material, the title compound (4) 2.19 was obtained in the same manner as in Example 13, (4).
g was obtained. Yield: 92%

IR (KBr) cm ^-1 : 2960, 1700, 163
0, 1550 NMR (CD ₃ OD + CDCl ₃ ) δ: 0.8 to 2.0 (12H,
m), 1.8 to 2.0 (3H, m), 2.7 to 2.9 (4H, m), 3.4 to 3.6 (1H,
m), 3.6-4.0 (5H, m), 5.5-5.7 (1H, m), 7.0-7.4 (4H, m),
7.41 (1H, d, J = 8.0Hz), 7.60 (1H, d, J = 8.0Hz), 8.29 (1H, d
d, J = 7.8 Hz, 1.8 Hz), 8.60 (1 H, dd, J = 5.6 Hz, 1.8 Hz) Specific rotation: [α] _D ²⁵ = −73.4 ° (c = 0.9, D
MSO)

Example 16 (1) (S) -4-dicyclohexylmethyl-1- (3
-Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Using 7.00 g of Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine as a raw material, 1-dicyclohexylmethylpiperazine is used instead of 1-isopropylpiperazine. In the same manner as in Example 13, (1), 6.43 g of the title compound (1) was obtained. Yield: 58%

NMR (CDCl ₃ ) δ: 0.9 to 1.3 (11H,
m), 1.49 (9H, s), 1.5-1.8 (11H, m), 1.9-2.0 (1H, m),
2.6-2.8 (4H, m), 3.3-3.9 (7H, m), 4.5-4.7 (1H, m), 5.7
2 (1H, bd)

(2) (S) -4-Dicyclohexylmethyl-1- (3-mesyloxy-2-t-butoxycarbonylamino) propionylpiperazine Using 6.00 g of the above compound (1) as a starting material, 2) In the same manner as in (i), the title compound (2)
6.31 g were obtained. Yield: 90%

NMR (CDCl ₃ ) δ: 0.9 to 1.4 (11H,
m), 1.49 (9H, s), 1.5-1.9 (11H, m), 1.9-2.1 (1H, m),
2.6 to 2.8 (4H, m), 3.08 (3H, s), 3.4 to 3.7 (4H, m), 4.2 to
4.4 (2H, m), 4.9 ~ 5.0 (1H, m), 5.52 (1H, bd)

(3) (R) -4-dicyclohexylmethyl-1- [3- (3-ethoxycarbonylpyridine-2
-Yl) thio-2-t-butoxycarbonylamino] propionylpiperazine Using 6.31 g of the compound (2) as a starting material, the title compound (3) was prepared in the same manner as in Example 13, (2) (ii).
4.39 g were obtained. Yield: 60%

NMR (CDCl ₃ ) δ: 1.40 (9H, s),
0.9-1.9 (25H, m), 1.9-2.1 (1H, m), 2.6-2.8 (4H, m),
3.0 to 3.3 (1H, m), 3.4 to 3.9 (5H, m), 4.3 to 4.5 (2H, m), 4.9
~ 5.1 (1H, m), 5.50 (1H, bd), 7.0 ~ 7.2 (1H, m), 8.2 ~ 8.4
(1H, m), 8.5-8.6 (1H, m)

(4) (R) -4-dicyclohexylmethyl-1- [3- (3-ethoxycarbonylpyridine-2
-Yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine Using 4.00 g of the above compound (3) as a starting material, the title compound (4) 3 was prepared in the same manner as in Example 13, (3). .51
g was obtained. Yield: 82%

NMR (CDCl ₃ ) δ: 0.9 to 1.3 (11H,
m), 1.40 (3H, t, J = 7.6Hz), 1.4 ~ 1.8 (11H, m), 1.8 ~ 2.0
(1H, m), 2.6 ~ 2.8 (4H, m), 3.4 ~ 3.9 (6H, m), 4.36 (2H, q,
J = 7.6Hz), 5.5 ~ 5.7 (1H, m), 6.90 (1H, s), 7.0 ~ 7.4 (4H,
m), 7.60 (1H, d, J = 7.8Hz), 7.70 (1H, d, J = 7.8Hz), 8.20 (1H
H, dd, J = 8.0Hz, 1.8Hz), 8.57 (1H, dd, J = 5.6Hz, 1.8Hz), 9.6
0 (1H, s)

(5) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4-dicyclohexylmethylpiperazine Using 3.00 g of the above compound (4) as a starting material, the title compound (5) 2.54 was obtained in the same manner as in Example 13, (4).
g was obtained. Yield: 89%

IR (KBr) cm ^-1 : 2920, 2850, 170
0, 1630, 1550 NMR (CDCl ₃ + CD ₃ OD) δ: 0.9 to 1.3 (11H,
m), 1.5-1.8 (11H, m), 2.0-2.2 (1H, m), 2.7-2.9 (4H,
m), 3.4 ~ 4.0 (6H, m), 5.5 ~ 5.7 (1H, m), 7.0 ~ 7.3 (4H, m),
7.40 (1H, d, J = 8.2Hz), 7.60 (1H, d, J = 8.0Hz), 8.27 (1H, d
d, J = 8.0 Hz, 1.8 Hz), 8.59 (1 H, dd, J = 5.4 Hz, 1.8 Hz) Specific rotation: [α] _D ²⁵ = −66.4 ° (c = 0.9, D
MSO)

Example 17 (1) (R) -4-diphenylmethyl-1- [3- (3
-Methoxycarbonylpyrazin-2-yl) thio-2-
10 ml of dichloromethane was added to 606 mg of (S-butoxycarbonylamino) propionylpiperazine (S) -4-diphenylmethyl-1- (2-t-butoxycarbonylamino-3-hydroxy) propionylpiperazine,
188 mg of triethylamine was added to dichloromethane 1
ml. 180 mg of methanesulfonyl chloride was added to this at −10 ° C. together with 4 ml of dichloromethane, and the mixture was stirred for 10 minutes. Then, 20 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 30 minutes. After removing the aqueous layer, the mixture was washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This was treated with 100 mg of sodium hydride and 392 mg of 2-methoxycarbonyl-3-mercaptopyrazine in 10 m of dimethylformamide.
The suspension was dropped at 0 ° C. under an argon stream,
Stirred for hours. Dilute the reaction with 30 ml of ethyl acetate,
The extract was washed with water (30 ml × 3) and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2) to obtain 352 mg of the title compound (1). Yield: 59%

NMR (CDCl ₃ ) δ: 1.37 (9H, s),
2.2 to 2.5 (4H, m), 3.0 to 3.2 (2H, m), 3.4 to 3.8 (4H, m), 4.0
0 (3H, s), 4.8 ~ 5.0 (1H, m), 5.52 (1H, d, J = 7.2Hz), 7.1 ~
7.5 (10H, m), 8.34 (1H, d, J = 2.3Hz), 8.42 (1H, d, J = 2.3Hz)

(2) (R) -4-diphenylmethyl-1
-[2- (indol-2-yl) carbonylamino-
3- (3-Methoxycarbonylpyrazin-2-yl) thio] propionylpiperazine To 170 mg of the above compound (1), 2 ml of 4N hydrogen chloride (ethyl acetate solution) was added, and the mixture was stirred at room temperature for 20 minutes. This was diluted with 5 ml of ethyl acetate, adjusted to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, 10 ml of dichloromethane was added, and 66 mg of indole-2-carboxylic acid, 66 mg of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate were added thereto. 47 mg was added, and the mixture was stirred at room temperature for 10 hours.
Ethyl acetate (20 ml) was added to the reaction solution, which was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue.
This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to obtain 99 mg of the title compound (2). Yield: 55%

NMR (CDCl ₃ ) δ: 2.2 to 2.5 (4H,
m), 3.3 to 3.5 (2H, m), 3.5 to 3.9 (5H, m), 3.88 (3H, s), 5.
5-5.7 (1H, m), 6.96 (1H, s), 7.05 (1H, dd, J = 14.3Hz, 14.3
Hz), 7.1 ~ 7.4 (11H, m), 7.57 (1H, d, J = 9.2Hz), 7.82 (1H, m
d, J = 9.2Hz), 8.25 (1H, d, J = 2.2Hz), 8.36 (1H, d, J = 2.2H
z), 9.72 (1H, s)

(3) (R) -1- [3- (3-carboxypyrazin-2-yl) thio-2- (indole-2-
Il) carbonylamino] propionyl-4-diphenylmethylpiperazine To 800 mg of the above compound (2), 2 ml of methanol, 1 ml of tetrahydrofuran and 1 ml of water were added and dissolved, and 200 mg of lithium hydroxide monohydrate was added thereto.
Stirred for minutes. The solvent of the reaction solution was distilled off under reduced pressure, diluted with 10 ml of dichloromethane, and washed with a 10% aqueous citric acid solution. After drying over anhydrous sodium sulfate, the solvent was distilled off,
730 mg of the title compound (3) was obtained. Yield: 93%

IR (KBr) cm ^-1 : 1630, 1550, 1450 NMR (CDCl ₃ ) δ: 2.4 to 2.6 (4H, m), 3.2 to 3.5
(2H, m), 3.6 to 3.9 (4H, m), 4.21 (1H, s), 5.52 (1H, bs), 6.
99 (1H, s), 7.08 (1H, d, J = 15.4Hz), 7.1 ~ 7.7 (12H, m),
7.45 (1H, d, J = 9.2Hz), 7.58 (1H, d, J = 9.2Hz), 8.23 (1H, b
s), 8.47 (1H, bs), 9.68 (1H, s) Specific rotation: [α] _D ²⁵ = −66.9 ° (c = 0.1, D
MSO)

Example 18 (1) (S) -4- (9-Fluorenyl) -1- (3-
Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Using 867 mg of Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine, 1- (9-fluorenyl) piperazine was used instead of 1-benzhydrylpiperazine. In the same manner as in Example 1, (1), 839 mg of the title compound (1) was obtained. Yield: 64%

NMR (CDCl ₃ ) δ: 1.39 (9H, s),
2.5 to 2.7 (4H, m), 3.3 to 3.4 (1H, m), 3.5 to 3.8 (6H, m), 4.
5 ~ 4.6 (1H, m), 4.86 (1H, s), 5.66 (1H, bd), 7.2 ~ 7.4 (4
H, m), 7.56 (2H, d, J = 7.6Hz), 7.68 (2H, d, J = 7.6Hz)

(2) (S) -4- (9-fluorenyl)
-1- (3-Mesyloxy-2-t-butoxycarbonylamino) propionylpiperazine Using 839 mg of the compound (1), (2) of Example 1
969 mg of the title compound (2) was obtained in the same manner as in the above. Yield: 98%

NMR (CDCl ₃ ) δ: 1.41 (9H, s), 2.
62 (4H, bs), 2.98 (3H, s), 3.5 ~ 3.7 (4H, m), 4.2 ~ 4.4 (2
H, m), 4.86 (1H, s), 4.8 ~ 5.0 (1H, m), 5.46 (1H, bd), 7.2
Up to 7.4 (4H, m), 7.59 (2H, bd), 7.68 (2H, d, J = 7.6Hz)

(3) (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionyl-4- (9-fluorenyl) piperazine The above compound (2 9) mg of the title compound (3) was obtained in the same manner as (3) of Example 1 using 940 mg of this compound and using ethyl 2-mercaptonicotinate instead of methyl 2-mercaptonicotinate. Yield: 88%

NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.
39 (3H, t, J = 7.1Hz), 2.65 (4H, bs), 3.0-3.2 (1H, m), 3.5
~ 3.9 (5H, m), 4.38 (2H, q, J = 7.1Hz), 4.86 (1H, s), 4.9 ~
5.1 (1H, m), 5.45 (1H, bd), 7.03 (1H, dd, J = 7.8Hz, 4.6Hz),
7.2 ~ 7.4 (4H, m), 7.60 (2H, d, J = 7.6Hz), 7.69 (2H, d, J =
7.6Hz), 8.20 (1H, dd, J = 7.8Hz, 1.8Hz), 8.40 (1H, dd, J = 4.6
Hz, 1.8Hz)

(4) (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionyl-4-
(9-Fluorenyl) piperazine Using 960 mg of the above compound (3), in the same manner as in (4) and (5) of Example 1, the title compound (4) 77
1 mg was obtained. Yield: 75%

NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.
0Hz), 2.64 (4H, bs), 3.3 ~ 3.5 (1H, m), 3.5 ~ 3.9 (5H, m),
4.31 (2H, q, J = 7.0Hz), 4.84 (1H, s), 5.5 ~ 5.7 (1H, m), 6.88
(1H, s), 7.0-7.4 (8H, m), 7.5-7.7 (6H, m), 8.16 (1H, dd,
J = 7.6Hz, 1.5Hz), 8.45 (1H, dd, J = 4.0Hz, 1.5Hz), 9.58 (1
H, s)

(5) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4- (9-fluorenyl) piperazine Using 750 mg of the above compound (4), the compound (6) of Example 1 was used.
In a similar manner to, 710 mg of the title compound (5) was obtained.
Yield: 99%

IR (KBr) cm ^-1 : 1700, 1620, 155
0, 1450 NMR (DMSO-d ₆ ) δ: 2.38 (2H, bs), 2.73 (2H, b
s), 3.0 to 3.9 (6H, m), 4.96 (1H, s), 5.1 to 5.4 (1H, m),
7.0 ~ 7.9 (14H, m), 8.22 (1H, d, J = 7.3Hz), 8.5 ~ 8.7 (1H,
m), 8.7-9.0 (1H, m), 11.57 (1H, s) Specific rotation: [α] _D ²⁵ = -121.1 ° (c = 0.9,
DMSO)

Example 19 (1) (S) -4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-
(3-Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Using 578 mg of Nt-butoxycarbonyl-O-tetrahydropyranyl-L-serine, 1- (10,11) was used instead of 1-benzhydrylpiperazine. -Dihydro-5
Using H-dibenzo [a, d] cyclohepten-5-yl) piperazine, 465 mg of the title compound (1) was obtained in the same manner as in (1) of Example 1. Yield: 50%

NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.
30 (4H, bs), 2.7 ~ 2.9 (2H, m), 3.2 ~ 3.4 (1H, m), 3.4 ~ 3.
6 (4H, m), 3.7-3.8 (2H, m), 3.95 (1H, s), 3.9-4.1 (2H,
m), 4.5-4.7 (1H, m), 5.68 (1H, bd), 7.0-7.2 (8H, m)

(2) (S) -4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1- (3-mesyloxy-2-t-butoxycarbonylamino) propionyl Piperazine Using 450 mg of the compound (1), (2) of Example 1
520 mg of the title compound (2) was obtained in the same manner as in the above. Yield: 99%

NMR (CDCl ₃ ) δ: 1.44 (9H, s),
2.2 to 2.4 (4H, m), 2.7 to 2.9 (2H, m), 3.00 (3H, s), 3.4 to
3.6 (4H, m), 3.94 (1H, s), 3.9 ~ 4.1 (2H, m), 4.2 ~ 4.4 (2
H, m), 4.8 ~ 5.0 (1H, m), 5.49 (1H, bd), 7.0 ~ 7.2 (8H, m)

(3) (R) -4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1- [3- (3-ethoxycarbonylpyridine-
2-yl) thio-2-t-butoxycarbonylamino]
Propionylpiperazine Using the above compound (2) (500 mg) and using ethyl 2-mercaptonicotinate instead of methyl 2-mercaptonicotinate, 534 mg of the title compound (3) was obtained in the same manner as in Example 1, (3). . Yield: 92%

NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.
39 (3H, t, J = 7.1Hz), 2.2 ~ 2.4 (4H, m), 2.7 ~ 2.9 (2H, m),
3.0 to 3.2 (1H, m), 3.4 to 3.8 (5H, m), 3.94 (1H, s), 3.9 to 4.
1 (2H, m), 4.38 (2H, q, J = 7.1Hz), 4.9 ~ 5.1 (1H, m), 5.46
(1H, bd), 7.0-7.2 (9H, m), 8.20 (1H, dd, J = 7.8Hz, 1.8Hz),
8.38 (1H, dd, J = 4.6Hz, 1.8Hz)

(4) (R) -4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1- [3- (3-ethoxycarbonylpyridine-
2-yl) thio-2- (indol-2-yl) carbonylamino] propionylpiperazine Using 530 mg of the above compound (3), the title compound (4) was prepared in the same manner as in (4) and (5) of Example 1. 419
mg was obtained. Yield: 74%

NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.
0Hz), 2.2 ~ 2.4 (4H, m), 2.7 ~ 2.9 (2H, m), 3.4 ~ 3.7 (6
H, m), 3.93 (1H, s), 4.0 ~ 4.1 (2H, m), 4.34 (2H, q, J = 7.0H
z), 5.5 ~ 5.7 (1H, m), 6.89 (1H, s), 7.0 ~ 7.4 (12H, m),
7.58 (1H, d, J = 7.9Hz), 7.70 (1H, d, J = 8.2Hz), 8.19 (1H, d
d, J = 7.9Hz, 1.8Hz), 8.46 (1H, dd, J = 4.6Hz, 1.8Hz), 9.58
(1H, s)

(5) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indole-2-
Yl) carbonylamino] propionyl-4- (10,
11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) piperazine Using 410 mg of the above compound (4), (6) of Example 1
358 mg of the title compound (5) was obtained in the same manner as in the above. Yield: 91%

IR (KBr) cm ^-1 : 1700, 1630, 155
0, 1450 NMR (DMSO-d 6) δ: 2.19 (4H, bs), 2.6~2.9
(2H, m), 3.1 to 3.8 (6H, m), 3.8 to 4.0 (2H, m), 3.95 (1H, s),
5.2 to 5.4 (1H, m), 7.0 to 7.3 (12H, m), 7.43 (1H, d, J = 8.2H
z), 7.64 (1H, d, J = 7.9Hz), 8.24 (1H, d, J = 7.6Hz), 8.5 ~
8.6 (1H, m), 8.8-8.9 (1H, m), 11.56 (1H, s) Specific rotation: [α] _D ²⁵ = −52.2 ° (c = 1.3, D
MSO)

Example 20 (1) (R) -1- [2- (5-chloroindole-2
-Yl) carbonylamino-3- (3-ethoxycarbonylpyridin-2-yl) thio] propionyl-4-diphenylmethylpiperidine (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) as a raw material Thio-2-t-butoxycarbonylamino] propionyl-4-diphenylmethylpiperidine ((3) of Example 2) was used and 6.05 g of 5-chloroindole-2-carboxylic acid was used instead of indole-2-carboxylic acid. Was used and 5.01 g of the title compound (1) was obtained in the same manner as in (4) and (5) of Example 1. Yield: 74%

NMR (CDCl ₃ ) δ: 1.0 to 1.4 (5H,
m), 1.5 ~ 1.7 (2H, m), 2.2 ~ 2.5 (1H, m), 2.65 (1H, bt), 3.
13 (1H, bt), 3.3 ~ 3.5 (2H, m), 3.6 ~ 3.8 (1H, m), 4.2 ~
4.5 (3H, m), 4.5 ~ 4.7 (1H, m), 5.5 ~ 5.7 (1H, m), 6.79 (1
H, s), 6.9 ~ 7.4 (14H, m), 7.49 (1H, s), 7.9 ~ 8.1 (1H,
m), 8.1 ~ 8.3 (1H, m), 8.3 ~ 8.5 (1H, m), 9.85,10.00 (Total 1H, s each)

(2) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-chloroindol-2-yl) carbonylamino] propionyl-4
-Diphenylmethylpiperidine Using 5.00 g of the above compound (1) as a raw material, 4.46 g of the title compound (2) in the same manner as in (6) of Example 1.
I got Yield: 93%

IR (KBr) cm ^-1 : 1700, 1620, 155
0, 1450 NMR (CDCl ₃ + CD ₃ OD) δ: 0.9 to 1.3 (2H,
m), 1.5 to 1.7 (2H, m), 2.3 to 2.8 (2H, m), 3.0 to 3.3 (1H,
m), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m), 4.3-4.6 (2H,
m), 5.4 ~ 5.7 (1H, m), 7.0 ~ 7.4 (14H, m), 7.46 (1H, bs),
8.2 to 8.4 (1H, m), 8.4 to 8.6 (1H, m) Specific rotation: [α] _D ²⁵ = -61.5 ° (c = 0.9, D
MSO)

Example 21 (1) (R) -4-diphenylmethyl-1- [3- (3
-Ethoxycarbonylpyridin-2-yl) thio-2-
(5-methoxyindol-2-yl) carbonylamino] propionylpiperidine As a raw material, (R) -1- [3- (3-ethoxycarbonylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionyl-4 Using 6.00 g of -diphenylmethylpiperidine ((3) of Example 2), 5-methoxyindole-2-carboxylic acid was used in place of indole-2-carboxylic acid, and (4) and (5) of Example 1 were used. )
5.18 g of the title compound (1) was obtained in the same manner as in the above. Yield: 77%

NMR (CDCl ₃ ) δ: 1.0 to 1.4 (5H,
m), 1.5-1.8 (2H, m), 2.2-2.5 (1H, m), 2.5-2.7 (1H, m),
2.9 to 3.2 (1H, m), 3.3 to 3.5 (2H, m), 3.6 to 3.8 (1H, m), 3.
81 (3H, s), 4.2 ~ 4.5 (3H, m), 4.5 ~ 4.7 (1H, m), 5.5 ~ 5.8
(1H, m), 6.83 (2H, s), 6.9 ~ 7.1 (2H, m), 7.1 ~ 7.4 (11H,
m), 7.6 ~ 7.8 (1H, m), 8.1 ~ 8.3 (1H, m), 8.46 (1H, dd, J =
12.4Hz, 4.1Hz), 9.64,9.70 (total 1H, each s)

(2) (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-methoxyindol-2-yl) carbonylamino] propionyl-
4-Diphenylmethylpiperidine Using 5.00 g of the above compound (1) as a raw material, 4.51 g of the title compound (2) in the same manner as in (6) of Example 1.
I got Yield: 94%

IR (KBr) cm ^-1 : 1700, 1620, 155
0, 1450 NMR (CDCl ₃ ) δ: 1.0 to 1.3 (2H, m), 1.5 to 1.9
(2H, m), 2.3 to 2.5 (1H, m), 2.5 to 2.8 (1H, m), 2.9 to 3.3 (2
H, m), 3.49 (1H, t, J = 9.9Hz), 3.73 (3H, s), 3.8 ~ 4.0 (1H,
m), 4.5-4.8 (2H, m), 5.5-5.7 (1H, m), 6.8-7.0 (3H, m),
6.88 (1H, s), 7.0 to 7.1 (1H, m), 7.1 to 7.4 (10H, m), 7.7
~ 7.9 (1H, m), 8.0 ~ 8.2 (1H, m), 8.43 (1H, dd, J = 11.0Hz, 3.
1 Hz), 10.75 (1H, s) Specific rotation: [α] _D ²⁵ = −55.8 ° (c = 1.2, D
MSO)

Example 22 (1) (R) -1- [3- (3-diisopropoxyphosphorylpyridin-2-yl) thio-2-t-butoxycarbonylamino] propionyl-4-diphenylmethylpiperazine (S) -4-diphenylmethyl-1- (3-
Using 2.20 g of (hydroxy-2-t-butoxycarbonylamino) propionylpiperazine ((1) of Example 1), diisopropyl (1,2-dihydro-2-thioxo-3-) was used instead of methyl 2-mercaptonicotinate. Using (pyridyl) phosphonate, (2) of Example 1
3.34 g of the title compound (1) was obtained in the same manner as in (3). Yield: 96%

NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 6.
1Hz), 1.28 (3H, d, J = 6.1Hz), 1.38 (9H, s), 1.39 (6H, d, J =
6.1Hz), 2.3 ~ 2.5 (4H, m), 3.1 ~ 3.3 (1H, m), 3.5 ~ 3.9
(5H, m), 4.24 (1H, s), 4.6 ~ 4.8 (2H, m), 4.9 ~ 5.1 (1H,
m), 5.51 (1H, bd), 7.02 (1H, ddd, J = 7.3Hz, 4.6Hz, 2.3Hz),
7.1 to 7.3 (6H, m), 7.3 to 7.5 (4H, m), 8.14 (1H, ddd, J = 1
4.1Hz, 7.3Hz, 2.3Hz), 8.34 (1H, ddd, J = 4.6Hz, 2.3Hz, 2.3H
z)

(2) (R) -1- [2-amino-3-
(3-Diisopropoxyphosphorylpyridin-2-yl) thio] propionyl-4-diphenylmethylpiperazine Using 1.34 g of the compound (1), (4) of Example 1
1.11 g of the title compound (2) was obtained in the same manner as in the above. Yield: 97%

NMR (CDCl ₃ ) δ: 1.27 (3H, d, J = 6.
3Hz), 1.29 (3H, d, J = 6.3Hz), 1.41 (6H, d, J = 6.3Hz), 1.86
(2H, bs), 2.3 to 2.6 (4H, m), 2.89 (1H, dd, J = 13.9Hz, 9.5H
z), 3.5-3.9 (5H, m), 4.04 (1H, dd, J = 9.5Hz, 3.4Hz), 4.
24 (1H, s), 4.6-4.8 (2H, m), 7.04 (1H, ddd, J = 7.3Hz, 4.6H
z, 2.3Hz), 7.1 to 7.3 (6H, m), 7.3 to 7.5 (4H, m), 8.14 (1
H, ddd, J = 14.1Hz, 7.3Hz, 2.3Hz), 8.30 (1H, ddd, J = 4.6Hz,
(2.3Hz, 2.3Hz)

(3) (R) -1- [3- (3-diisopropoxyphosphorylpyridin-2-yl) thio-2-
(Indol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 1.11 g of the compound (2), (5) of Example 1
1.37 g of the title compound (3) was obtained in the same manner as in the above. Yield: 99%

NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6.
2Hz), 1.20 (3H, d, J = 6.2Hz), 1.29 (3H, d, J = 6.2Hz), 1.34
(3H, d, J = 6.2Hz), 2.3 ~ 2.5 (4H, m), 3.4 ~ 3.9 (6H, m), 4.
22 (1H, s), 4.6 ~ 4.8 (2H, m), 5.4 ~ 5.6 (1H, m), 6.85 (1H,
s), 7.0-7.5 (14H, m), 7.58 (1H, d, J = 7.9Hz), 7.69 (1H,
d, J = 8.2Hz), 8.12 (1H, ddd, J = 14.1Hz, 7.3Hz, 2.3Hz), 8.4
2 (1H, ddd, J = 4.6Hz, 2.3Hz, 2.3Hz), 9.51 (1H, bs)

(4) (R) -4-diphenylmethyl-1
-[3- (3-phosphonopyridin-2-yl) thio-2
-(Indol-2-yl) carbonylamino] propionylpiperazine 458 mg of the above compound (3) was added to dimethylformamide 6
Then, 1.16 g of bromotrimethylsilane was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was added to water, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 334 mg of the title compound (3). Yield: 82%

IR (KBr) cm ^-1 : 1640, 1540, 146
0, 1380 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.3 to
3.9 (6H, m), 4.37 (1H, s), 5.1 to 5.3 (1H, m), 7.0 to 7.5 (15
H, m), 7.62 (1H, d, J = 7.6Hz), 7.9 ~ 8.1 (1H, m), 8.3 ~ 8.
4 (1H, m), 8.90 (1H, d, J = 7.9Hz), 11.56 (1H, s) Specific rotation: [α] _D ²⁵ = -40.3 ° (c = 1.2, D
MSO)

Next, the results of the anti-CCK activity test and the binding test of the compound of the present invention will be shown. Anti-cholecystokinin (CC) in guinea pig isolated ileum
K) Action After killing and exsanguinating male guinea pigs (Hartley strain), the excised ileum pieces were placed in a Tyrode solution (136.9 mM, NaCl 136.9 mM, containing 37 ° C. and 5% CO ₂ mixed O ₂ gas).
KCl 2.68 mM, CaCl ₂ 1.8 mM, Mg
_{Cl 2 1.05mM, NaH 2 PO 4} 0.42m
M, NaHCO ₃ 11.9 mM, glucose 5.55
The suspension was suspended by applying 0.5 g of tension to a Magnus tube containing 30 ml of (mM). The change in shrinkage was recorded isotonic via soot on smoke paper. Leave this ileum piece for 30 minutes, 1 ×
10 ^-8 M CCK-8 was added and shrunk. After washing, this was repeated several times, and after the contraction of CCK-8 was stabilized, the test compound was added, and 5 minutes later, 1 × 10 ⁻⁸ M of CCK-8 was added and the contraction was measured. The contraction by CCK-8 and the contraction by CCK-8 in the presence of a different concentration of the test compound were compared, and the IC ₅₀ value [the concentration of the test compound that inhibits the contraction of CCK-8 by 50%] is shown in Table 2. . The compound numbers in Table 2 indicate the target compounds according to the example numbers.

[0191]

[Table 2]

Peripheral Receptor (CCK-A) and Central Receptor (CCK-B) Binding Experiments Van Dijik et al. (The Journal of Neuroscience, Volume 4, 1021-1033)
Preparation of CCK receptor standard and [ ³ H] -CCK-8 binding inhibition experiment were carried out according to the method described in J. Am. The pancreas and cerebrum of a male rat (Nippon Medical) weighing 250 to 300 g, which was sacrificed by decapitation, were removed and immersed in ice-cold Hepes (HEPES) buffer. These were suspended with a potter-type homogenizer and then centrifuged at 48,000 × g for 10 minutes. The obtained residue was suspended by adding ice-cold Hepes buffer and centrifuged again at 48,000 × g for 10 minutes. The resulting residue was taken up in ice-cold incubation buffer. Aliquot of homogenate 1m
1 in the presence of 0.2 nM [ ³ H] -CCK-8 and the test compound or in the presence of solvent alone (for measuring total binding) or 1 μM cold CCK-8 (for measuring non-specific binding).
Incubated at 60 ° C for 60 minutes. Then, Whatman glass GF / B immersed in Hepes buffer
The reaction solution was quickly suction-filtered using a filter, and the filter was washed with ice-cold Hepes buffer. Next, the glass filter was placed in Aquasol-2, and the radioactivity was measured with a liquid scintillation counter. The specific binding amount to the CCK receptor was determined from the difference between the total binding amount and the non-specific binding amount, and the IC ₅₀ value was calculated from the inhibition rate of the specific binding amount by the test compound. Table 3 shows the results. The compound numbers in Table 3 indicate the target compounds according to the example numbers.

[0193]

[Table 3]

[0194]

The compound of the present invention exhibits a potent anti-CCK activity in a nanomolar order value (10 ^-9 M) in vitro. That is, the guinea pig isolated ileum in Table 2 (in vitro
The IC ₅₀ values of the compound of the present invention), as shown in the experimental examples in Table 2, was 7.2 × 10 ^-9 M (compound 17). Also, as shown in the experimental examples of Table 3 of the present invention,
In the binding experiment of CCK-A receptor prepared from rat pancreatic cell membrane, the compound of the present invention showed an IC ₅₀ value of 5.1 × 10 5
^-9 M (compound 1), 4.3 × 10 ^-9 M (compound 2),
5.0 × 10 ⁻⁹ M (Compound 12), 6.0 × 10 ⁻⁹ M
(Compound 10) showed a strong activity of 9.0 × 10 ⁻⁹ M (Compound 19). That is, the compound of the present invention showed about 165 to 350 times stronger activity than CR1505 in the binding experiment. In addition, these compounds have relatively weak binding to CCK-B receptor derived from rat brain cell membrane, and showed high selectivity to CCK-A receptor by about 20 to 130,000 times. Therefore, the compound of the present invention is useful as an agent for preventing and treating pancreatic cancer, gastric ulcer, duodenal ulcer, peptic ulcer, colitis, biliary dysfunction, especially acute pancreatitis.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 401/14 209 C07D 401/14 209 403/12 209 403/12 209 C07F 9/6558 C07F 9/6558 (58) Fields surveyed (Int.Cl. ⁶ , DB name) C07D 209/42 C07D 401/12 209 C07D 401/14 209 C07D 403/12 209 C07F 9/6558 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A compound of the general formula (I) Wherein, (1) A is CH or nitrogen atom, form a piperidine ring or piperazine ring taken together with N in the formula
And occupies position 4 with respect to said N at position 1 in the ring, (2) R
₁ is (i) a linear or branched alkyl group having 1 to 4 carbon atoms,
(Ii) a cyclohexyl group, (iii) an unsubstituted or substituted phenyl group substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms, (iv) a pyridyl group, and (v) two R ₁ groups.
Represents a group selected from the group consisting of a dibenzo [a, d] cycloheptenyl group and a fluorenyl group bonded together with a> CH— group, and (3) R ₂ represents (i) phenyl substituted with a carboxyl group or a substituted carboxyl group. A group selected from the group consisting of a group, a pyridyl group, a pyrazyl group, and (ii) a phosphonopyridyl group; (4) R ₃ is unsubstituted or a halogen atom, a hydroxy group, The indolyl group substituted by a group selected from the group consisting of a methoxycarbonylethyl group is shown. And a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ₁ is a phenyl group substituted by a fluorine atom or a methoxy group. 3. The compound according to claim 1, wherein R ₃ is an indolyl group substituted by a group selected from the group consisting of a chlorine atom, a hydroxy group and a methoxy group. 4. The compound according to claim 1, which is (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine. A compound as described. 5. The compound according to claim 1, which is (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (indol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperidine. A compound as described. 6. It is (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-chloroindol-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperidine. A compound according to claim 1. 7. (R) -1- [3- (3-carboxypyridin-2-yl) thio-2- (5-methoxyindol-2-yl) carbonylamino] propionyl-4-
The compound according to claim 1, which is diphenylmethylpiperidine.